dbSNP rs10900297: RET:c.-196C>A (chr10-43077063-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020975.6(RET):c.-196C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 744,828 control chromosomes in the GnomAD database, including 55,965 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 13195 hom., cov: 33)

Exomes 𝑓: 0.36 ( 42770 hom. )

Consequence

RET
NM_020975.6 upstream_gene

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.315

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 10-43077063-C-A is Benign according to our data. Variant chr10-43077063-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 368899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.-196C>A		upstream_gene_variant		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.-196C>A		upstream_gene_variant		5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

AF:

0.414

AC:

62655

AN:

151278

Hom.:

13165

Cov.:

show subpopulations

Gnomad AFR

AF:

0.476

Gnomad AMI

AF:

0.484

Gnomad AMR

AF:

0.433

Gnomad ASJ

AF:

0.328

Gnomad EAS

AF:

0.315

Gnomad SAS

AF:

0.416

Gnomad FIN

AF:

0.362

Gnomad MID

AF:

0.388

Gnomad NFE

AF:

0.391

Gnomad OTH

AF:

0.405

GnomAD4 exome

AF:

0.362

AC:

215063

AN:

593442

Hom.:

42770

Cov.:

AF XY:

0.363

AC XY:

104807

AN XY:

288616

show subpopulations

Gnomad4 AFR exome

AF:

0.456

Gnomad4 AMR exome

AF:

0.425

Gnomad4 ASJ exome

AF:

0.319

Gnomad4 EAS exome

AF:

0.264

Gnomad4 SAS exome

AF:

0.420

Gnomad4 FIN exome

AF:

0.360

Gnomad4 NFE exome

AF:

0.362

Gnomad4 OTH exome

AF:

0.370

GnomAD4 genome

AF:

0.414

AC:

62733

AN:

151386

Hom.:

13195

Cov.:

AF XY:

0.415

AC XY:

30709

AN XY:

74058

show subpopulations

Gnomad4 AFR

AF:

0.476

Gnomad4 AMR

AF:

0.434

Gnomad4 ASJ

AF:

0.328

Gnomad4 EAS

AF:

0.316

Gnomad4 SAS

AF:

0.416

Gnomad4 FIN

AF:

0.362

Gnomad4 NFE

AF:

0.391

Gnomad4 OTH

AF:

0.406

Alfa

AF:

0.398

Hom.:

1474

Bravo

AF:

0.424

Asia WGS

AF:

0.360

AC:

1217

AN:

3384

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pheochromocytoma

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal hypodysplasia/aplasia 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hirschsprung Disease, Dominant

Benign:1

Jun 14, 2016

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

-0.76

CADD

Benign

2.7

DANN

Benign

0.68

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