6-3076950-A-T

Position:

• chr6-3076950-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

The NM_001354930.2(RIPK1):​c.127A>T​(p.Ile43Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000912 in 1,611,694 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000084 (1 hom.)
• Consequence: RIPK1 NM_001354930.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.42

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_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38593936).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000158 (24/151704) while in subpopulation AMR AF= 0.000722 (11/15228). AF 95% confidence interval is 0.000404. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPK1	NM_001354930.2	c.127A>T	p.Ile43Phe	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.127A>T	p.Ile43Phe	missense_variant	2/11	5	NM_001354930.2	ENSP00000259808	P1

Frequencies

GnomAD3 genomes AF: 0.000152 AC: 23 AN: 151588 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000172 AC: 43 AN: 250556 Hom.: 0 AF XY: 0.000192 AC XY: 26 AN XY: 135482

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000468

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000842 AC: 123 AN: 1459990 Hom.: 1 Cov.: 34 AF XY: 0.000101 AC XY: 73 AN XY: 726274

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000538

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151704 Hom.: 0 Cov.: 30 AF XY: 0.000175 AC XY: 13 AN XY: 74144

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000722

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 16, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 43 of the RIPK1 protein (p.Ile43Phe). This variant is present in population databases (rs184897325, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with RIPK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 809859). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D
Eigen	Benign	0.12
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.66	N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.061	T;T
Polyphen		1.0	D;D
Vest4		0.70
MVP		0.80
MPC		1.0
ClinPred		0.12	T
GERP RS		1.9
Varity_R		0.75
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs184897325; hg19: chr6-3077184;