14-24337267-C-T

Position:

• chr14-24337267-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006871.4(RIPK3):​c.1094G>A​(p.Cys365Tyr) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIPK3 NM_006871.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.65

Genes affected

RIPK3 (HGNC:10021): (receptor interacting serine/threonine kinase 3) The product of this gene is a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases, and contains a C-terminal domain unique from other RIP family members. The encoded protein is predominantly localized to the cytoplasm, and can undergo nucleocytoplasmic shuttling dependent on novel nuclear localization and export signals. It is a component of the tumor necrosis factor (TNF) receptor-I signaling complex, and can induce apoptosis and weakly activate the NF-kappaB transcription factor. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025148004).
• BP6: Variant 14-24337267-C-T is Benign according to our data. Variant chr14-24337267-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3154528.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPK3	NM_006871.4	c.1094G>A	p.Cys365Tyr	missense_variant	8/10	ENST00000216274.10	NP_006862.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPK3	ENST00000216274.10	c.1094G>A	p.Cys365Tyr	missense_variant	8/10	1	NM_006871.4	ENSP00000216274	P1
RIPK3	ENST00000554756.1	c.*436G>A		3_prime_UTR_variant, NMD_transcript_variant	8/10	1		ENSP00000452328
RIPK3	ENST00000554569.1	c.137G>A	p.Cys46Tyr	missense_variant	1/2	2		ENSP00000451840

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.062
DANN	Benign	0.36
DEOGEN2	Benign	0.097	.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.019	N
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.025	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	.;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-4.4	D;N
REVEL	Benign	0.12
Sift	Benign	0.45	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0	.;B
Vest4		0.16
MutPred		0.23		.;Gain of catalytic residue at K363 (P = 0.0059);
MVP		0.10
MPC		0.59
ClinPred		0.043	T
GERP RS		-5.1
Varity_R		0.035
gMVP		0.15

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: rs1001294847; hg19: chr14-24806473;