10-43109129-G-T

Variant names:

• chr10-43109129-G-T
• rs776223166
• NM_020975.6:c.1162G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020975.6(RET):​c.1162G>T​(p.Val388Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. V388A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.255
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06893861).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	NM_020975.6	MANE Select	c.1162G>T	p.Val388Phe	missense	Exon 6 of 20	NP_066124.1
	RET	NM_001406743.1		c.1162G>T	p.Val388Phe	missense	Exon 6 of 21	NP_001393672.1
	RET	NM_001406744.1		c.1162G>T	p.Val388Phe	missense	Exon 6 of 20	NP_001393673.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RET	ENST00000355710.8	TSL:5 MANE Select	c.1162G>T	p.Val388Phe	missense	Exon 6 of 20	ENSP00000347942.3
	RET	ENST00000340058.6	TSL:1	c.1162G>T	p.Val388Phe	missense	Exon 6 of 19	ENSP00000344798.4
	RET	ENST00000713926.1		c.1033G>T	p.Val345Phe	missense	Exon 6 of 19	ENSP00000519223.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple endocrine neoplasia type 2B Uncertain:1

Sep 27, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence favors the benign nature of this variant, however the evidence is insufficent to prove its benign nature. The following ACMG criteria were applied in classifying this variant: BP4,.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	0.14
DANN	Benign	0.97
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.26
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Benign	0.071	T
Sift4G	Benign	0.064	T
Polyphen		0.0020	B
Vest4		0.17
MutPred		0.31		Gain of sheet (P = 0.039)
MVP		0.40
MPC		0.27
ClinPred		0.039	T
GERP RS		0.47
Varity_R		0.14
gMVP		0.59
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs776223166; hg19: chr10-43604577;