rs76759170

Positions:

• chr10-43129860-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020975.6(RET):​c.*1591G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 396,966 control chromosomes in the GnomAD database, including 459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (142 hom., cov: 33)
  • Exomes 𝑓: 0.044 (317 hom.)
• Consequence: RET NM_020975.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.487

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 10-43129860-G-A is Benign according to our data. Variant chr10-43129860-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 299937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.*1591G>A		3_prime_UTR_variant	20/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.*1591G>A		3_prime_UTR_variant	20/20	5	NM_020975.6	P4
RET	ENST00000615310.5	c.*3106G>A		3_prime_UTR_variant	17/17	5
RET	ENST00000683007.1	n.5899G>A		non_coding_transcript_exon_variant	16/16

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5916 AN: 152144 Hom.: 142 Cov.: 33

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.0531

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0867

Gnomad FIN AF: 0.0315

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0476

Gnomad OTH AF: 0.0540

GnomAD4 exome AF: 0.0444 AC: 10873 AN: 244702 Hom.: 317 Cov.: 0 AF XY: 0.0453 AC XY: 5612 AN XY: 124016

Gnomad4 AFR exome AF: 0.0208

Gnomad4 AMR exome AF: 0.0322

Gnomad4 ASJ exome AF: 0.0568

Gnomad4 EAS exome AF: 0.00101

Gnomad4 SAS exome AF: 0.0904

Gnomad4 FIN exome AF: 0.0388

Gnomad4 NFE exome AF: 0.0510

Gnomad4 OTH exome AF: 0.0475

GnomAD4 genome AF: 0.0389 AC: 5925 AN: 152264 Hom.: 142 Cov.: 33 AF XY: 0.0392 AC XY: 2918 AN XY: 74436

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.0365

Gnomad4 ASJ AF: 0.0531

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0870

Gnomad4 FIN AF: 0.0315

Gnomad4 NFE AF: 0.0476

Gnomad4 OTH AF: 0.0530

Alfa AF: 0.0422 Hom.: 39

Bravo AF: 0.0377

Asia WGS AF: 0.0320 AC: 110 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Renal hypodysplasia/aplasia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hirschsprung disease, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2021

- -

Multiple endocrine neoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.8
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs76759170; hg19: chr10-43625308;