NM_020975.6:c.2939+7G>A

Variant names:

• chr10-43123815-G-A
• rs374565577
• NM_020975.6:c.2939+7G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_020975.6(RET):​c.2939+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: RET NM_020975.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002833
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: -0.639
• Publications: 0 publications found

Genes affected

RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

RET Gene-Disease associations (from GenCC):

• familial medullary thyroid carcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hirschsprung disease, susceptibility to, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-43123815-G-A is Benign according to our data. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358. Variant chr10-43123815-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477358.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.2939+7G>A		splice_region_variant, intron_variant	Intron 17 of 19	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2939+7G>A		splice_region_variant, intron_variant	Intron 17 of 19	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251346 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461686 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727154

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pheochromocytoma Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hirschsprung disease, susceptibility to, 1 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Renal hypodysplasia/aplasia 1 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Multiple endocrine neoplasia Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia, type 2 Benign:1

Aug 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.24
DANN	Benign	0.50
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs374565577; hg19: chr10-43619263;