14-24338272-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006871.4(RIPK3):c.641T>C(p.Val214Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,372,590 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: RIPK3 NM_006871.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPK3	NM_006871.4	c.641T>C	p.Val214Ala	missense_variant	5/10	ENST00000216274.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPK3	ENST00000216274.10	c.641T>C	p.Val214Ala	missense_variant	5/10	1	NM_006871.4	P1
RIPK3	ENST00000557624.1	n.1403T>C		non_coding_transcript_exon_variant	3/3	1
RIPK3	ENST00000554756.1	c.641T>C	p.Val214Ala	missense_variant, NMD_transcript_variant	5/10	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183982 Hom.: 0 AF XY: 0.0000104 AC XY: 1 AN XY: 96586

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000618

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1372590 Hom.: 0 Cov.: 32 AF XY: 0.00000149 AC XY: 1 AN XY: 672644

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000257

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000843 AC: 1

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

Oct 14, 2023

The c.641T>C (p.V214A) alteration is located in exon 5 (coding exon 5) of the RIPK3 gene. This alteration results from a T to C substitution at nucleotide position 641, causing the valine (V) at amino acid position 214 to be replaced by an alanine (A). 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	Uncertain	0.34
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.58	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.63	N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.96	D
Vest4		0.62
MutPred		0.64		Gain of catalytic residue at L210 (P = 0);
MVP		0.68
MPC		0.64
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.41
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs751571187; hg19: chr14-24807478;