rs2272990

Positions:

• chr6-3076907-T-A
• chr6-3076907-T-C
• chr6-3076907-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001354930.2(RIPK1):​c.84T>A​(p.Phe28Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RIPK1 NM_001354930.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23

Genes affected

RIPK1 (HGNC:10019): (receptor interacting serine/threonine kinase 1) This gene encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. The encoded protein plays a role in inflammation and cell death in response to tissue damage, pathogen recognition, and as part of developmental regulation. RIPK1/RIPK3 kinase-mediated necrosis is referred to as necroptosis. Genetic disruption of this gene in mice results in death shortly after birth. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPK1	NM_001354930.2	c.84T>A	p.Phe28Leu	missense_variant	2/11	ENST00000259808.9	NP_001341859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPK1	ENST00000259808.9	c.84T>A	p.Phe28Leu	missense_variant	2/11	5	NM_001354930.2	ENSP00000259808	P1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460870 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.6	H;H
MutationTaster	Benign	0.000037	P;P;P
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		1.0	D;D
Vest4		0.66
MutPred		0.89		Gain of catalytic residue at F28 (P = 0.0876);Gain of catalytic residue at F28 (P = 0.0876);
MVP		0.77
MPC		0.85
ClinPred		0.99	D
GERP RS		-2.6
Varity_R		0.77
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2272990; hg19: chr6-3077141;