10-43106458-C-T

Variant names:

• chr10-43106458-C-T
• rs760322514
• NM_020975.6:c.950C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_020975.6(RET):​c.950C>T​(p.Thr317Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T317R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.47
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37297624).

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.950C>T	p.Thr317Met	missense	Exon 5 of 20	NP_066124.1	P07949-1
	RET	NM_001406743.1		c.950C>T	p.Thr317Met	missense	Exon 5 of 21	NP_001393672.1	P07949-1
	RET	NM_001406744.1		c.950C>T	p.Thr317Met	missense	Exon 5 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.950C>T	p.Thr317Met	missense	Exon 5 of 20	ENSP00000347942.3	P07949-1
	RET	ENST00000340058.6	TSL:1	c.950C>T	p.Thr317Met	missense	Exon 5 of 19	ENSP00000344798.4	P07949-2
	RET	ENST00000713926.1		c.821C>T	p.Thr274Met	missense	Exon 5 of 19	ENSP00000519223.1	A0AAQ5BH28

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248134 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461094 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726804

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Hirschsprung disease, susceptibility to, 1 (1)
-	1	-	Multiple endocrine neoplasia, type 2 (1)
-	1	-	RET-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	0.16
Eigen_PC	Benign	0.011
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.098	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.34
MutPred		0.41		Loss of sheet (P = 0.0817)
MVP		0.81
MPC		0.70
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.13
gMVP		0.87
Mutation Taster		=73/27	polymorphism

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: rs760322514; hg19: chr10-43601906; COSMIC: COSV100392441; COSMIC: COSV100392441;