rs1800859

Variant names:

• chr10-43102379-C-A
• rs1800859
• NM_020975.6:c.375C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-43102379-C-A
• chr10-43102379-C-G
• chr10-43102379-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_020975.6(RET):​c.375C>A​(p.Val125Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,614,248 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V125V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0085 (10 hom., cov: 33)
  • Exomes 𝑓: 0.010 (105 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -0.206
• Publications: 9 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: G2P, Orphanet
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, 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 -16 ACMG points.

• BP6: Variant 10-43102379-C-A is Benign according to our data. Variant chr10-43102379-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00845 (1288/152370) while in subpopulation AMR AF = 0.0157 (240/15306). AF 95% confidence interval is 0.0141. There are 10 homozygotes in GnomAd4. There are 601 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020975.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.375C>A	p.Val125Val	synonymous	Exon 3 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.375C>A	p.Val125Val	synonymous	Exon 3 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.375C>A	p.Val125Val	synonymous	Exon 3 of 20	NP_001393673.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.375C>A	p.Val125Val	synonymous	Exon 3 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.375C>A	p.Val125Val	synonymous	Exon 3 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000638465.2	TSL:5	c.415C>A	p.Leu139Ile	missense	Exon 3 of 3	ENSP00000491505.2	A0A1W2PPN7

Frequencies

GnomAD3 genomes AF: 0.00846 AC: 1288 AN: 152252 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00736 AC: 1850 AN: 251300 AF XY: 0.00732

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00867

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00239

Gnomad FIN exome AF: 0.00287

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0104 AC: 15137 AN: 1461878 Hom.: 105 Cov.: 32 AF XY: 0.0102 AC XY: 7438 AN XY: 727240

African (AFR) AF: 0.00170 AC: 57 AN: 33480

American (AMR) AF: 0.00935 AC: 418 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 339 AN: 26136

East Asian (EAS) AF: 0.00103 AC: 41 AN: 39700

South Asian (SAS) AF: 0.000835 AC: 72 AN: 86256

European-Finnish (FIN) AF: 0.00307 AC: 164 AN: 53408

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5768

European-Non Finnish (NFE) AF: 0.0120 AC: 13337 AN: 1112010

Other (OTH) AF: 0.0102 AC: 614 AN: 60396

GnomAD4 genome AF: 0.00845 AC: 1288 AN: 152370 Hom.: 10 Cov.: 33 AF XY: 0.00806 AC XY: 601 AN XY: 74522

African (AFR) AF: 0.00233 AC: 97 AN: 41590

American (AMR) AF: 0.0157 AC: 240 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 835 AN: 68036

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.00937 Hom.: 5

Bravo AF: 0.00900

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0115

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	2	Multiple endocrine neoplasia, type 2 (2)
-	-	2	Pheochromocytoma (2)
-	-	1	Aganglionic megacolon (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hirschsprung disease, susceptibility to, 1 (1)
-	-	1	Multiple endocrine neoplasia (1)
-	-	1	Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 (1)
-	-	1	Multiple endocrine neoplasia type 2B (1)
-	-	1	Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Benign	0.61
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1800859; hg19: chr10-43597827; COSMIC: COSV60705120;