chr10-43125103-G-A

Variant names:

• chr10-43125103-G-A
• rs2742236
• NM_020975.6:c.3039+121G>A

Variant summary

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

The NM_020975.6(RET):​c.3039+121G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 883,598 control chromosomes in the GnomAD database, including 133,351 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 0.56 (24258 hom., cov: 31)
  • Exomes 𝑓: 0.54 (109093 hom.)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388
• Publications: 14 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.3039+121G>A		intron_variant	Intron 18 of 19	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.3039+121G>A		intron_variant	Intron 18 of 19	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84762 AN: 151720 Hom.: 24228 Cov.: 31

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.535

GnomAD4 exome AF: 0.537 AC: 393082 AN: 731760 Hom.: 109093 AF XY: 0.528 AC XY: 203232 AN XY: 384990

African (AFR) AF: 0.618 AC: 11711 AN: 18946

American (AMR) AF: 0.430 AC: 15052 AN: 34968

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 10694 AN: 20794

East Asian (EAS) AF: 0.285 AC: 9189 AN: 32254

South Asian (SAS) AF: 0.333 AC: 21947 AN: 65878

European-Finnish (FIN) AF: 0.530 AC: 24415 AN: 46070

Middle Eastern (MID) AF: 0.444 AC: 1380 AN: 3106

European-Non Finnish (NFE) AF: 0.589 AC: 279195 AN: 473734

Other (OTH) AF: 0.541 AC: 19499 AN: 36010

GnomAD4 genome AF: 0.559 AC: 84842 AN: 151838 Hom.: 24258 Cov.: 31 AF XY: 0.551 AC XY: 40885 AN XY: 74190

African (AFR) AF: 0.621 AC: 25707 AN: 41386

American (AMR) AF: 0.499 AC: 7632 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 1746 AN: 3464

East Asian (EAS) AF: 0.291 AC: 1496 AN: 5140

South Asian (SAS) AF: 0.313 AC: 1505 AN: 4810

European-Finnish (FIN) AF: 0.525 AC: 5528 AN: 10522

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.580 AC: 39367 AN: 67924

Other (OTH) AF: 0.538 AC: 1132 AN: 2104

Alfa AF: 0.539 Hom.: 5387

Bravo AF: 0.563

Asia WGS AF: 0.336 AC: 1173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.41
PhyloP100		-0.39
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: rs2742236; hg19: chr10-43620551; COSMIC: COSV60691630;