10-43114671-G-A

Variant names:

• chr10-43114671-G-A
• rs1799939
• NM_020975.6:c.2071G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_020975.6(RET):​c.2071G>A​(p.Gly691Ser) variant causes a missense change. The variant allele was found at a frequency of 0.184 in 1,612,242 control chromosomes in the GnomAD database, including 29,287 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G691R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.17 (2471 hom., cov: 31)
  • Exomes 𝑓: 0.19 (26816 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:27 O:1
• Conservation: PhyloP100: 4.41
• Publications: 239 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005253911).
• BP6: Variant 10-43114671-G-A is Benign according to our data. Variant chr10-43114671-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 24934.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

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.2071G>A	p.Gly691Ser	missense	Exon 11 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.2071G>A	p.Gly691Ser	missense	Exon 11 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.2071G>A	p.Gly691Ser	missense	Exon 11 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.2071G>A	p.Gly691Ser	missense	Exon 11 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.2071G>A	p.Gly691Ser	missense	Exon 11 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.1807G>A	p.Gly603Ser	missense	Exon 11 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25745 AN: 151742 Hom.: 2472 Cov.: 31

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.210 AC: 52572 AN: 250098 AF XY: 0.208

Gnomad AFR exome AF: 0.0983

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.185 AC: 270502 AN: 1460382 Hom.: 26816 Cov.: 36 AF XY: 0.187 AC XY: 135943 AN XY: 726526

African (AFR) AF: 0.0963 AC: 3224 AN: 33478

American (AMR) AF: 0.338 AC: 15130 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5195 AN: 26136

East Asian (EAS) AF: 0.0943 AC: 3744 AN: 39700

South Asian (SAS) AF: 0.257 AC: 22161 AN: 86258

European-Finnish (FIN) AF: 0.212 AC: 11009 AN: 51970

Middle Eastern (MID) AF: 0.254 AC: 1463 AN: 5768

European-Non Finnish (NFE) AF: 0.178 AC: 197680 AN: 1111974

Other (OTH) AF: 0.180 AC: 10896 AN: 60384

GnomAD4 genome AF: 0.170 AC: 25747 AN: 151860 Hom.: 2471 Cov.: 31 AF XY: 0.173 AC XY: 12841 AN XY: 74188

African (AFR) AF: 0.101 AC: 4190 AN: 41466

American (AMR) AF: 0.248 AC: 3795 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 698 AN: 3464

East Asian (EAS) AF: 0.105 AC: 540 AN: 5120

South Asian (SAS) AF: 0.243 AC: 1166 AN: 4794

European-Finnish (FIN) AF: 0.230 AC: 2422 AN: 10534

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.182 AC: 12344 AN: 67898

Other (OTH) AF: 0.179 AC: 378 AN: 2106

Alfa AF: 0.181 Hom.: 8534

Bravo AF: 0.170

TwinsUK AF: 0.182 AC: 674

ALSPAC AF: 0.181 AC: 699

ESP6500AA AF: 0.103 AC: 455

ESP6500EA AF: 0.185 AC: 1587

ExAC AF: 0.202 AC: 24557

Asia WGS AF: 0.169 AC: 586 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.194

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (10)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	1	2	Multiple endocrine neoplasia type 2A (3)
-	-	3	Multiple endocrine neoplasia, type 2 (3)
-	-	3	not provided (3)
-	-	2	Pheochromocytoma (2)
-	-	1	Hirschsprung disease, susceptibility to, 1 (1)
-	-	1	Multiple endocrine neoplasia (1)
-	-	1	Multiple endocrine neoplasia type 2B (1)
-	-	1	Prostate neoplasm (1)
-	-	1	Renal hypodysplasia/aplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.21
Sift	Benign	0.18	T
Sift4G	Benign	0.12	T
Polyphen		0.062	B
Vest4		0.045
MPC		0.20
ClinPred		0.015	T
GERP RS		-1.1
Varity_R		0.039
gMVP		0.50
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1799939; hg19: chr10-43610119; COSMIC: COSV60687096; COSMIC: COSV60687096;