NM_020975.6:c.50_58dupTGCTGCTGC

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1

The NM_020975.6(RET):c.50_58dupTGCTGCTGC(p.Leu17_Leu19dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,511,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

RET
NM_020975.6 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 0.417

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6

Variant 10-43077301-T-TTGCTGCTGC is Benign according to our data. Variant chr10-43077301-T-TTGCTGCTGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216728.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000176 (24/1359912) while in subpopulation AMR AF= 0.000598 (20/33462). AF 95% confidence interval is 0.000395. There are 0 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.50_58dupTGCTGCTGC	p.Leu17_Leu19dup	disruptive_inframe_insertion	Exon 1 of 20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 link	c.50_58dupTGCTGCTGC	p.Leu17_Leu19dup	disruptive_inframe_insertion	Exon 1 of 20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151732

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

108732

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

60254

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000611

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000909

GnomAD4 exome

AF:

0.0000176

AC:

AN:

1359912

Hom.:

Cov.:

AF XY:

0.0000149

AC XY:

AN XY:

670738

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000598

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000596

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.37e-7

Gnomad4 OTH exome

AF:

0.0000176

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74108

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Feb 26, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Jul 20, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 14, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Multiple endocrine neoplasia type 2A

Uncertain:1

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia, type 2

Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.50_58dup, results in the insertion of 3 amino acid(s) of the RET protein (p.Leu17_Leu19dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs768132465, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 216728). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Feb 27, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RET c.50_58dupTGCTGCTGC (p.Leu17_Leu19dup) results in an in-frame duplication that is predicted to duplicate three amino acids into the encoded protein. The variant allele was found at a frequency of 0.00015 in 108732 control chromosomes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 phenotype (3.7e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.50_58dupTGCTGCTGC in individuals affected with Multiple Endocrine Neoplasia Type 2 and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=5). Based on the evidence outlined above, the variant was classified as likely benign. -

Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1

Benign:1

Jun 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over