rs10900297

Variant names:

• chr10-43077063-C-A
• rs10900297
• ENST00000794440.1:n.49G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-43077063-C-A
• chr10-43077063-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000794440.1(ENSG00000303432):​n.49G>T variant causes a splice region, non coding transcript exon 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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: ENSG00000303432 ENST00000794440.1 splice_region, non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.315
• Publications: 22 publications found

Genes affected

ENSG00000303432 (HGNC:):

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: Benign. The variant received -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	c.-196C>A		upstream_gene_variant		ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.-196C>A		upstream_gene_variant		5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62655 AN: 151278 Hom.: 13165 Cov.: 33

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.: 8 AF XY: 0.363 AC XY: 104807 AN XY: 288616

African (AFR) AF: 0.456 AC: 5622 AN: 12324

American (AMR) AF: 0.425 AC: 2533 AN: 5960

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 3290 AN: 10298

East Asian (EAS) AF: 0.264 AC: 5638 AN: 21344

South Asian (SAS) AF: 0.420 AC: 6774 AN: 16116

European-Finnish (FIN) AF: 0.360 AC: 6436 AN: 17880

Middle Eastern (MID) AF: 0.407 AC: 733 AN: 1802

European-Non Finnish (NFE) AF: 0.362 AC: 174297 AN: 481366

Other (OTH) AF: 0.370 AC: 9740 AN: 26352

GnomAD4 genome AF: 0.414 AC: 62733 AN: 151386 Hom.: 13195 Cov.: 33 AF XY: 0.415 AC XY: 30709 AN XY: 74058

African (AFR) AF: 0.476 AC: 19687 AN: 41330

American (AMR) AF: 0.434 AC: 6613 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1136 AN: 3464

East Asian (EAS) AF: 0.316 AC: 1616 AN: 5120

South Asian (SAS) AF: 0.416 AC: 2002 AN: 4816

European-Finnish (FIN) AF: 0.362 AC: 3775 AN: 10420

Middle Eastern (MID) AF: 0.403 AC: 117 AN: 290

European-Non Finnish (NFE) AF: 0.391 AC: 26494 AN: 67706

Other (OTH) AF: 0.406 AC: 856 AN: 2106

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

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
PhyloP100		-0.32
PromoterAI		0.019	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10900297; hg19: chr10-43572511;