Genetic Variant NM_020975.6:c.*1969T>C (chr10-43130238-T-C) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_020975.6(RET):c.*1969T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0474 in 388,468 control chromosomes in the GnomAD database, including 563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.044 ( 183 hom., cov: 33)

Exomes 𝑓: 0.050 ( 380 hom. )

Consequence

RET
NM_020975.6 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0130

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 10-43130238-T-C is Benign according to our data. Variant chr10-43130238-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 13954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.*1969T>C		3_prime_UTR_variant	Exon 20 of 20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RET	ENST00000355710.8 link	c.*1969T>C	3_prime_UTR_variant	Exon 20 of 20	5	NM_020975.6	ENSP00000347942.3	P07949-1
RET	ENST00000615310.5 link	c.*3484T>C	3_prime_UTR_variant	Exon 17 of 17	5		ENSP00000480088.2	A0A087WWB1
RET	ENST00000683007.1 link	n.6277T>C	non_coding_transcript_exon_variant	Exon 16 of 16

Frequencies

GnomAD3 genomes

AF:

0.0438

AC:

6661

AN:

152232

Hom.:

183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0242

Gnomad AMI

AF:

0.0998

Gnomad AMR

AF:

0.0385

Gnomad ASJ

AF:

0.0536

Gnomad EAS

AF:

0.000961

Gnomad SAS

AF:

0.0887

Gnomad FIN

AF:

0.0399

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0557

Gnomad OTH

AF:

0.0587

GnomAD4 exome

AF:

0.0498

AC:

11760

AN:

236118

Hom.:

380

Cov.:

AF XY:

0.0505

AC XY:

6037

AN XY:

119564

show subpopulations

Gnomad4 AFR exome

AF:

0.0221

Gnomad4 AMR exome

AF:

0.0350

Gnomad4 ASJ exome

AF:

0.0559

Gnomad4 EAS exome

AF:

0.000988

Gnomad4 SAS exome

AF:

0.0897

Gnomad4 FIN exome

AF:

0.0478

Gnomad4 NFE exome

AF:

0.0578

Gnomad4 OTH exome

AF:

0.0516

GnomAD4 genome

AF:

0.0438

AC:

6670

AN:

152350

Hom.:

183

Cov.:

AF XY:

0.0437

AC XY:

3259

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0244

Gnomad4 AMR

AF:

0.0384

Gnomad4 ASJ

AF:

0.0536

Gnomad4 EAS

AF:

0.000963

Gnomad4 SAS

AF:

0.0890

Gnomad4 FIN

AF:

0.0399

Gnomad4 NFE

AF:

0.0557

Gnomad4 OTH

AF:

0.0577

Alfa

AF:

0.0550

Hom.:

180

Bravo

AF:

0.0417

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16986122) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hirschsprung disease, protection against

Benign:1

Feb 01, 2007

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pheochromocytoma

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Multiple endocrine neoplasia type 2A

Benign:1

Nov 14, 2017

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal hypodysplasia/aplasia 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hirschsprung disease, susceptibility to, 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Multiple endocrine neoplasia

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

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

-0.44

CADD

Benign

8.0

DANN

Benign

0.81

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

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