6-3076953-A-G

Variant names:

• chr6-3076953-A-G
• rs1393554291
• NM_001354930.2:c.130A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001354930.2(RIPK1):​c.130A>G​(p.Met44Val) 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 benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M44L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RIPK1 NM_001354930.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.782
• Publications: 1 publications found

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]

RIPK1 Gene-Disease associations (from GenCC):

• immunodeficiency 57

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autoinflammation with episodic fever and lymphadenopathy

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15157205).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354930.2. 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
	RIPK1	NM_001354930.2	MANE Select	c.130A>G	p.Met44Val	missense	Exon 2 of 11	NP_001341859.1	Q13546-1
	RIPK1	NM_003804.6		c.130A>G	p.Met44Val	missense	Exon 2 of 11	NP_003795.2	Q13546-1
	RIPK1	NM_001354931.2		c.130A>G	p.Met44Val	missense	Exon 2 of 10	NP_001341860.1	Q13546-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK1	ENST00000259808.9	TSL:5 MANE Select	c.130A>G	p.Met44Val	missense	Exon 2 of 11	ENSP00000259808.3	Q13546-1
	RIPK1	ENST00000380409.3	TSL:1	c.130A>G	p.Met44Val	missense	Exon 2 of 10	ENSP00000369773.3	Q13546-2
	RIPK1	ENST00000967583.1		c.130A>G	p.Met44Val	missense	Exon 2 of 12	ENSP00000637642.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250392 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.96e-7 AC: 1 AN: 1435778 Hom.: 0 Cov.: 34 AF XY: 0.00000140 AC XY: 1 AN XY: 713888

African (AFR) AF: 0.00 AC: 0 AN: 32774

American (AMR) AF: 0.00 AC: 0 AN: 43850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25316

East Asian (EAS) AF: 0.00 AC: 0 AN: 38016

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5226

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095822

Other (OTH) AF: 0.00 AC: 0 AN: 58696

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.3	N
PhyloP100		0.78
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.12
Sift	Uncertain	0.021	D
Sift4G	Benign	0.12	T
Polyphen		0.31	B
Vest4		0.20
MutPred		0.48		Gain of methylation at K45 (P = 0.029)
MVP		0.54
MPC		0.23
ClinPred		0.084	T
GERP RS		2.7
Varity_R		0.13
gMVP		0.46
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1393554291; hg19: chr6-3077187;