10-43128177-A-T

Variant names:

• chr10-43128177-A-T
• NM_020975.6:c.3253A>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020975.6(RET):​c.3253A>T​(p.Thr1085Ser) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050099462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.3253A>T	p.Thr1085Ser	missense_variant	Exon 20 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.3253A>T	p.Thr1085Ser	missense_variant	Exon 20 of 20	5	NM_020975.6	ENSP00000347942.3
RET	ENST00000615310.5	c.*1423A>T		3_prime_UTR_variant	Exon 17 of 17	5		ENSP00000480088.2
RET	ENST00000683007.1	n.4216A>T		non_coding_transcript_exon_variant	Exon 16 of 16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

May 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1085S variant (also known as c.3253A>T), located in coding exon 20 of the RET gene, results from an A to T substitution at nucleotide position 3253. The threonine at codon 1085 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.79
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.13
Sift	Benign	0.70	T
Sift4G	Benign	0.90	T
Polyphen		0.0010	B
Vest4		0.048
MutPred		0.25		Gain of glycosylation at T1085 (P = 0.0259);
MVP		0.39
MPC		0.18
ClinPred		0.056	T
GERP RS		1.5
Varity_R		0.029
gMVP		0.24

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-43623625; COSMIC: COSV60712785; COSMIC: COSV60712785;