14-24336257-G-T

Variant names:

• chr14-24336257-G-T
• rs3212254
• NM_006871.4:c.1475C>A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 24 publications found

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]

ENSG00000258973 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006871.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK3	NM_006871.4	MANE Select	c.1475C>A	p.Pro492Gln	missense	Exon 10 of 10	NP_006862.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK3	ENST00000216274.10	TSL:1 MANE Select	c.1475C>A	p.Pro492Gln	missense	Exon 10 of 10	ENSP00000216274.5
	RIPK3	ENST00000554756.1	TSL:1	n.*817C>A		non_coding_transcript_exon	Exon 10 of 10	ENSP00000452328.1
	RIPK3	ENST00000554756.1	TSL:1	n.*817C>A		3_prime_UTR	Exon 10 of 10	ENSP00000452328.1

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

GnomAD2 exomes AF: 0.0733 AC: 18324 AN: 250032 AF XY: 0.0726

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 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

African (AFR) AF: 0.205 AC: 6869 AN: 33472

American (AMR) AF: 0.0437 AC: 1953 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0624 AC: 1629 AN: 26126

East Asian (EAS) AF: 0.104 AC: 4115 AN: 39696

South Asian (SAS) AF: 0.0889 AC: 7667 AN: 86216

European-Finnish (FIN) AF: 0.0420 AC: 2236 AN: 53266

Middle Eastern (MID) AF: 0.0614 AC: 354 AN: 5768

European-Non Finnish (NFE) AF: 0.0549 AC: 61089 AN: 1111792

Other (OTH) AF: 0.0691 AC: 4175 AN: 60386

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

African (AFR) AF: 0.204 AC: 8465 AN: 41432

American (AMR) AF: 0.0530 AC: 801 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.0593 AC: 205 AN: 3456

East Asian (EAS) AF: 0.129 AC: 670 AN: 5178

South Asian (SAS) AF: 0.0890 AC: 429 AN: 4822

European-Finnish (FIN) AF: 0.0412 AC: 437 AN: 10600

Middle Eastern (MID) AF: 0.0420 AC: 12 AN: 286

European-Non Finnish (NFE) AF: 0.0551 AC: 3716 AN: 67462

Other (OTH) AF: 0.0786 AC: 165 AN: 2100

Alfa AF: 0.0688 Hom.: 1996

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 v4.9

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
PhyloP100		1.3
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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