14-24336183-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006871.4(RIPK3):​c.1549G>A​(p.Gly517Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,611,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

RIPK3
NM_006871.4 missense

Scores

2
1
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.235
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.061020464).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RIPK3NM_006871.4 linkc.1549G>A p.Gly517Arg missense_variant Exon 10 of 10 ENST00000216274.10 NP_006862.2 Q9Y572-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RIPK3ENST00000216274.10 linkc.1549G>A p.Gly517Arg missense_variant Exon 10 of 10 1 NM_006871.4 ENSP00000216274.5 Q9Y572-1
RIPK3ENST00000554756.1 linkn.*891G>A non_coding_transcript_exon_variant Exon 10 of 10 1 ENSP00000452328.1 Q9Y572-3
RIPK3ENST00000554756.1 linkn.*891G>A 3_prime_UTR_variant Exon 10 of 10 1 ENSP00000452328.1 Q9Y572-3
ENSG00000258973ENST00000555591.1 linkn.358+702G>A intron_variant Intron 2 of 3 4

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152176
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000319
AC:
8
AN:
250674
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135516
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad SAS exome
AF:
0.0000982
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.000327
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1459502
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
725814
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000505
Gnomad4 SAS exome
AF:
0.0000465
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000720
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152176
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000416
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 08, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1549G>A (p.G517R) alteration is located in exon 10 (coding exon 10) of the RIPK3 gene. This alteration results from a G to A substitution at nucleotide position 1549, causing the glycine (G) at amino acid position 517 to be replaced by an arginine (R). 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
Benign
0.092
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.039
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.015
N
M_CAP
Benign
0.068
D
MetaRNN
Benign
0.061
T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
0.55
N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
-1.0
N
REVEL
Benign
0.21
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.058
B
Vest4
0.090
MutPred
0.20
Gain of solvent accessibility (P = 0.0037);
MVP
0.55
MPC
0.35
ClinPred
0.086
T
GERP RS
-2.4
Varity_R
0.19
gMVP
0.024

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs752152656; hg19: chr14-24805389; COSMIC: COSV53478475; COSMIC: COSV53478475; API