rs78935588

chr10-43114519-C-Achr10-43114519-C-Gchr10-43114519-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_020975.6(RET):c.1919C>A(p.Ala640Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A640G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_020975.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43114519-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 13942.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1919C>A	p.Ala640Asp	missense_variant	11/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1919C>A	p.Ala640Asp	missense_variant	11/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.84	T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.61	D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.3	M;.;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.0	N;D;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.047	D;D;D
Polyphen		0.92	P;.;D
Vest4		0.64
MutPred		0.60		Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);
MVP		0.86
MPC		0.42
ClinPred		0.79	D
GERP RS		1.4
Varity_R		0.25
gMVP		0.85

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-43609967;