10-43127485-T-C

Variant names:

• chr10-43127485-T-C
• rs2565200
• ENST00000340058.6:c.*731T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000340058.6(RET):​c.*731T>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 0.827 in 1,032,618 control chromosomes in the GnomAD database, including 355,142 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.84 (54289 hom., cov: 32)
  • Exomes 𝑓: 0.83 (300853 hom.)
• Consequence: RET ENST00000340058.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0820
• Publications: 23 publications found

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 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.3188-627T>C		intron_variant	Intron 19 of 19	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.3188-627T>C		intron_variant	Intron 19 of 19	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.839 AC: 127638 AN: 152064 Hom.: 54222 Cov.: 32

Gnomad AFR AF: 0.946

Gnomad AMI AF: 0.920

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.823

Gnomad OTH AF: 0.825

GnomAD4 exome AF: 0.825 AC: 726423 AN: 880436 Hom.: 300853 Cov.: 26 AF XY: 0.825 AC XY: 335428 AN XY: 406822

African (AFR) AF: 0.955 AC: 16664 AN: 17448

American (AMR) AF: 0.794 AC: 2443 AN: 3076

Ashkenazi Jewish (ASJ) AF: 0.771 AC: 6113 AN: 7924

East Asian (EAS) AF: 0.485 AC: 5430 AN: 11188

South Asian (SAS) AF: 0.746 AC: 12840 AN: 17212

European-Finnish (FIN) AF: 0.833 AC: 285 AN: 342

Middle Eastern (MID) AF: 0.786 AC: 1487 AN: 1892

European-Non Finnish (NFE) AF: 0.831 AC: 656449 AN: 790414

Other (OTH) AF: 0.799 AC: 24712 AN: 30940

GnomAD4 genome AF: 0.840 AC: 127769 AN: 152182 Hom.: 54289 Cov.: 32 AF XY: 0.836 AC XY: 62213 AN XY: 74412

African (AFR) AF: 0.946 AC: 39268 AN: 41518

American (AMR) AF: 0.808 AC: 12349 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 2654 AN: 3470

East Asian (EAS) AF: 0.500 AC: 2586 AN: 5174

South Asian (SAS) AF: 0.711 AC: 3427 AN: 4822

European-Finnish (FIN) AF: 0.822 AC: 8704 AN: 10592

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.823 AC: 55969 AN: 68000

Other (OTH) AF: 0.824 AC: 1741 AN: 2112

Alfa AF: 0.827 Hom.: 20949

Bravo AF: 0.846

Asia WGS AF: 0.624 AC: 2172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.3
DANN	Benign	0.83
PhyloP100		0.082
Mutation Taster		=100/0	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: rs2565200; hg19: chr10-43622933; COSMIC: COSV60689476;