14-24336257-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006871.4(RIPK3):c.1475C>A(p.Pro492Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0652 in 1,612,796 control chromosomes in the GnomAD database, including 4,541 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.099 (1094 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3447 hom.)
• Consequence: RIPK3 NM_006871.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012404621).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPK3	NM_006871.4	c.1475C>A	p.Pro492Gln	missense_variant	10/10	ENST00000216274.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPK3	ENST00000216274.10	c.1475C>A	p.Pro492Gln	missense_variant	10/10	1	NM_006871.4	P1
RIPK3	ENST00000554756.1	c.*817C>A		3_prime_UTR_variant, NMD_transcript_variant	10/10	1

Frequencies

GnomAD3 genomes AF: 0.0991 AC: 14987 AN: 151238 Hom.: 1095 Cov.: 32

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0531

Gnomad ASJ AF: 0.0593

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.0889

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.0455

Gnomad NFE AF: 0.0551

Gnomad OTH AF: 0.0789

GnomAD3 exomes AF: 0.0733 AC: 18324 AN: 250032 Hom.: 988 AF XY: 0.0726 AC XY: 9805 AN XY: 135134

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.0411

Gnomad ASJ exome AF: 0.0639

Gnomad EAS exome AF: 0.144

Gnomad SAS exome AF: 0.0885

Gnomad FIN exome AF: 0.0415

Gnomad NFE exome AF: 0.0555

Gnomad OTH exome AF: 0.0647

GnomAD4 exome AF: 0.0616 AC: 90087 AN: 1461436 Hom.: 3447 Cov.: 32 AF XY: 0.0623 AC XY: 45300 AN XY: 726998

Gnomad4 AFR exome AF: 0.205

Gnomad4 AMR exome AF: 0.0437

Gnomad4 ASJ exome AF: 0.0624

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.0889

Gnomad4 FIN exome AF: 0.0420

Gnomad4 NFE exome AF: 0.0549

Gnomad4 OTH exome AF: 0.0691

GnomAD4 genome AF: 0.0991 AC: 14995 AN: 151360 Hom.: 1094 Cov.: 32 AF XY: 0.0981 AC XY: 7261 AN XY: 74042

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.0530

Gnomad4 ASJ AF: 0.0593

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.0890

Gnomad4 FIN AF: 0.0412

Gnomad4 NFE AF: 0.0551

Gnomad4 OTH AF: 0.0786

Alfa AF: 0.0632 Hom.: 792

Bravo AF: 0.105

TwinsUK AF: 0.0475 AC: 176

ALSPAC AF: 0.0537 AC: 207

ESP6500AA AF: 0.201 AC: 886

ESP6500EA AF: 0.0565 AC: 486

ExAC AF: 0.0763 AC: 9264

Asia WGS AF: 0.0870 AC: 302 AN: 3478

EpiCase AF: 0.0608

EpiControl AF: 0.0574

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	12
Dann	Benign	0.77
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.13	N
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.060
MPC		0.50
ClinPred		0.020	T
GERP RS		1.9
Varity_R		0.064
gMVP		0.069

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

LitVar

Other links and lift over

dbSNP: rs3212254; hg19: chr14-24805463; COSMIC: COSV53475639; COSMIC: COSV53475639;