rs3026750

Variant names:

• chr10-43112308-G-A
• rs3026750
• NM_020975.6:c.1648+84G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-43112308-G-A
• chr10-43112308-G-T

Variant summary

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

The NM_020975.6(RET):​c.1648+84G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 1,539,160 control chromosomes in the GnomAD database, including 444,138 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 0.77 (45598 hom., cov: 35)
  • Exomes 𝑓: 0.76 (398540 hom.)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.70
• Publications: 10 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.83 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.1648+84G>A		intron_variant	Intron 8 of 19	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1648+84G>A		intron_variant	Intron 8 of 19	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117002 AN: 151628 Hom.: 45538 Cov.: 35

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.819

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.780

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.750

GnomAD4 exome AF: 0.756 AC: 1048831 AN: 1387412 Hom.: 398540 AF XY: 0.752 AC XY: 514590 AN XY: 684634

African (AFR) AF: 0.832 AC: 26130 AN: 31404

American (AMR) AF: 0.767 AC: 27329 AN: 35626

Ashkenazi Jewish (ASJ) AF: 0.718 AC: 18014 AN: 25072

East Asian (EAS) AF: 0.533 AC: 19018 AN: 35660

South Asian (SAS) AF: 0.647 AC: 50754 AN: 78496

European-Finnish (FIN) AF: 0.761 AC: 35850 AN: 47090

Middle Eastern (MID) AF: 0.722 AC: 3134 AN: 4340

European-Non Finnish (NFE) AF: 0.770 AC: 825947 AN: 1072220

Other (OTH) AF: 0.742 AC: 42655 AN: 57504

GnomAD4 genome AF: 0.772 AC: 117124 AN: 151748 Hom.: 45598 Cov.: 35 AF XY: 0.769 AC XY: 57033 AN XY: 74136

African (AFR) AF: 0.837 AC: 34660 AN: 41390

American (AMR) AF: 0.760 AC: 11617 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.716 AC: 2479 AN: 3460

East Asian (EAS) AF: 0.510 AC: 2627 AN: 5146

South Asian (SAS) AF: 0.622 AC: 2997 AN: 4818

European-Finnish (FIN) AF: 0.780 AC: 8198 AN: 10516

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.767 AC: 52011 AN: 67840

Other (OTH) AF: 0.751 AC: 1581 AN: 2104

Alfa AF: 0.756 Hom.: 5341

Bravo AF: 0.777

Asia WGS AF: 0.598 AC: 2081 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.36
DANN	Benign	0.54
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3026750; hg19: chr10-43607756;