chr14-24337878-A-G

Position:

• chr14-24337878-A-G

Variant summary

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

The NM_006871.4(RIPK3):​c.827T>C​(p.Phe276Ser) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RIPK3 NM_006871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.63

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 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, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPK3	NM_006871.4	c.827T>C	p.Phe276Ser	missense_variant	6/10	ENST00000216274.10	NP_006862.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPK3	ENST00000216274.10	c.827T>C	p.Phe276Ser	missense_variant	6/10	1	NM_006871.4	ENSP00000216274	P1
RIPK3	ENST00000554756.1	c.*169T>C		3_prime_UTR_variant, NMD_transcript_variant	6/10	1		ENSP00000452328

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.827T>C (p.F276S) alteration is located in exon 6 (coding exon 6) of the RIPK3 gene. This alteration results from a T to C substitution at nucleotide position 827, causing the phenylalanine (F) at amino acid position 276 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.57	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.47
Sift	Benign	0.064	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.69		Gain of catalytic residue at L280 (P = 5e-04);
MVP		0.85
MPC		0.89
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.49
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr14-24807084;