rs75075748

chr10-43118381-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020975.6(RET):c.2293T>C(p.Ser765Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S765F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 5.03

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.2293T>C	p.Ser765Pro	missense_variant	13/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.2293T>C	p.Ser765Pro	missense_variant	13/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hirschsprung disease, susceptibility to, 1 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 27, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.028	D;D
Polyphen		1.0	D;D
Vest4		0.46
MutPred		0.84		Gain of catalytic residue at S765 (P = 0.0067);Gain of catalytic residue at S765 (P = 0.0067);
MVP		0.92
MPC		0.88
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs75075748; hg19: chr10-43613829;