Genetic Variant RIPK3:p.Arg422* (chr14-24337097-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006871.4(RIPK3):c.1264C>T(p.Arg422*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,611,564 control chromosomes in the GnomAD database, including 7 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 7 hom. )

Consequence

RIPK3
NM_006871.4 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.282

Publications

14 publications found

Variant links:

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]

RIPK3 links:

ENSG00000258973 (HGNC:):

ENSG00000258973 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK3	NM_006871.4	MANE Select	c.1264C>T	p.Arg422*	stop_gained	Exon 8 of 10	NP_006862.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIPK3	ENST00000216274.10	TSL:1 MANE Select	c.1264C>T	p.Arg422*	stop_gained	Exon 8 of 10	ENSP00000216274.5	Q9Y572-1
RIPK3	ENST00000554756.1	TSL:1	n.*606C>T		non_coding_transcript_exon	Exon 8 of 10	ENSP00000452328.1	Q9Y572-3
RIPK3	ENST00000554756.1	TSL:1	n.*606C>T		3_prime_UTR	Exon 8 of 10	ENSP00000452328.1	Q9Y572-3

Frequencies

GnomAD3 genomes

AF:

0.00181

AC:

276

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00263

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00163

AC:

407

AN:

249232

AF XY:

0.00153

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000252

Gnomad NFE exome

AF:

0.00226

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00223

AC:

3247

AN:

1459316

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1600

AN XY:

726048

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33470

American (AMR)

AF:

0.00369

AC:

165

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000185

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000275

AC:

AN:

50994

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00263

AC:

2928

AN:

1111918

Other (OTH)

AF:

0.00167

AC:

101

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

188

376

565

753

941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00181

AC:

276

AN:

152248

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41520

American (AMR)

AF:

0.00412

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00263

AC:

179

AN:

68028

Other (OTH)

AF:

0.00332

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00212

Hom.:

Bravo

AF:

0.00186

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00156

AC:

190

EpiCase

AF:

0.00218

EpiControl

AF:

0.00279

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.048

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.032

PhyloP100

0.28

Vest4

0.78

GERP RS

0.73

PromoterAI

-0.0066

Neutral

(source)

Mutation Taster

=155/45

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over