rs139790943

Variant names:

• chr10-43105111-T-C
• rs139790943
• NM_020975.6:c.785T>C
• RET p.Val262Ala

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_020975.6(RET):​c.785T>C​(p.Val262Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000215 in 1,612,474 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. V262M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:9
• Conservation: PhyloP100: 5.52
• Publications: 11 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: G2P, Orphanet, ClinGen
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23900184).
• BP6: Variant 10-43105111-T-C is Benign according to our data. Variant chr10-43105111-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41845.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000256 (39/152180) while in subpopulation AMR AF = 0.000457 (7/15302). AF 95% confidence interval is 0.000243. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.785T>C	p.Val262Ala	missense	Exon 4 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.785T>C	p.Val262Ala	missense	Exon 4 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.785T>C	p.Val262Ala	missense	Exon 4 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.785T>C	p.Val262Ala	missense	Exon 4 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.785T>C	p.Val262Ala	missense	Exon 4 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.656T>C	p.Val219Ala	missense	Exon 4 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000247 AC: 61 AN: 246512 AF XY: 0.000291

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000967

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.000211 AC: 308 AN: 1460294 Hom.: 2 Cov.: 36 AF XY: 0.000222 AC XY: 161 AN XY: 726582

African (AFR) AF: 0.000149 AC: 5 AN: 33468

American (AMR) AF: 0.0000895 AC: 4 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86238

European-Finnish (FIN) AF: 0.0000383 AC: 2 AN: 52184

Middle Eastern (MID) AF: 0.00626 AC: 36 AN: 5750

European-Non Finnish (NFE) AF: 0.000184 AC: 205 AN: 1111832

Other (OTH) AF: 0.000348 AC: 21 AN: 60352

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74396

African (AFR) AF: 0.0000482 AC: 2 AN: 41526

American (AMR) AF: 0.000457 AC: 7 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 67988

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000507 Hom.: 0

Bravo AF: 0.000253

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	2	1	Hereditary cancer-predisposing syndrome (3)
-	1	2	Multiple endocrine neoplasia type 2A (3)
-	2	1	Multiple endocrine neoplasia, type 2 (3)
-	2	-	not specified (2)
-	1	-	Aganglionic megacolon (1)
-	1	-	Hirschsprung disease, susceptibility to, 1 (1)
-	1	-	Malignant tumor of breast (1)
-	-	1	Multiple endocrine neoplasia (1)
-	-	1	Pheochromocytoma (1)
-	1	-	Renal hypodysplasia/aplasia 1 (1)
-	-	1	RET-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Varity_R		0.64
gMVP		0.94
Mutation Taster		=40/60	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs139790943;

hg19: chr10-43600559;