rs34106261

Variant names:

• chr14-24337696-G-A
• rs34106261
• NM_006871.4:c.899C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-24337696-G-A
• chr14-24337696-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006871.4(RIPK3):​c.899C>T​(p.Thr300Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0486 in 1,609,770 control chromosomes in the GnomAD database, including 2,317 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.063 (411 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1906 hom.)
• Consequence: RIPK3 NM_006871.4 missense, splice_region
• Scores: Splicing: ADA: 0.00005966
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.84
• Publications: 16 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017099977).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK3	NM_006871.4	c.899C>T	p.Thr300Met	missense_variant, splice_region_variant	Exon 7 of 10	ENST00000216274.10	NP_006862.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK3	ENST00000216274.10	c.899C>T	p.Thr300Met	missense_variant, splice_region_variant	Exon 7 of 10	1	NM_006871.4	ENSP00000216274.5
RIPK3	ENST00000554756.1	n.*241C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 10	1		ENSP00000452328.1
RIPK3	ENST00000554756.1	n.*241C>T		3_prime_UTR_variant	Exon 7 of 10	1		ENSP00000452328.1

Frequencies

GnomAD3 genomes AF: 0.0632 AC: 9617 AN: 152150 Hom.: 407 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0526

Gnomad FIN AF: 0.0646

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0699

GnomAD2 exomes AF: 0.0491 AC: 12231 AN: 249322 AF XY: 0.0486

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0300

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.0647

Gnomad NFE exome AF: 0.0455

Gnomad OTH exome AF: 0.0520

GnomAD4 exome AF: 0.0470 AC: 68575 AN: 1457502 Hom.: 1906 Cov.: 32 AF XY: 0.0474 AC XY: 34393 AN XY: 725230

African (AFR) AF: 0.107 AC: 3582 AN: 33382

American (AMR) AF: 0.0328 AC: 1464 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2959 AN: 26098

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39674

South Asian (SAS) AF: 0.0514 AC: 4427 AN: 86098

European-Finnish (FIN) AF: 0.0657 AC: 3507 AN: 53356

Middle Eastern (MID) AF: 0.0806 AC: 464 AN: 5756

European-Non Finnish (NFE) AF: 0.0442 AC: 48967 AN: 1108294

Other (OTH) AF: 0.0531 AC: 3201 AN: 60256

GnomAD4 genome AF: 0.0633 AC: 9641 AN: 152268 Hom.: 411 Cov.: 32 AF XY: 0.0646 AC XY: 4811 AN XY: 74456

African (AFR) AF: 0.104 AC: 4339 AN: 41546

American (AMR) AF: 0.0501 AC: 767 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0518 AC: 250 AN: 4826

European-Finnish (FIN) AF: 0.0646 AC: 685 AN: 10600

Middle Eastern (MID) AF: 0.0719 AC: 21 AN: 292

European-Non Finnish (NFE) AF: 0.0449 AC: 3051 AN: 68020

Other (OTH) AF: 0.0691 AC: 146 AN: 2112

Alfa AF: 0.0514 Hom.: 644

Bravo AF: 0.0639

TwinsUK AF: 0.0375 AC: 139

ALSPAC AF: 0.0436 AC: 168

ESP6500AA AF: 0.0992 AC: 437

ESP6500EA AF: 0.0476 AC: 409

ExAC AF: 0.0497 AC: 6039

Asia WGS AF: 0.0280 AC: 98 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.0060
DANN	Benign	0.50
DEOGEN2	Benign	0.11	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0057	N
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.46	N
PhyloP100		-3.8
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.24
Sift	Benign	0.092	T
Sift4G	Benign	0.15	T
Polyphen		0.048	B
Vest4		0.023
MPC		0.16
ClinPred		0.0097	T
GERP RS		-9.3
PromoterAI		-0.010	Neutral
Varity_R		0.018
gMVP		0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000060
dbscSNV1_RF	Benign	0.038
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: rs34106261; hg19: chr14-24806902; COSMIC: COSV53474329; COSMIC: COSV53474329;