6-3076953-A-C

Variant names:

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

Variant summary

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

The NM_001317061.3(RIPK1):​c.-474A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,435,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RIPK1 NM_001317061.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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=0.08576274).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317061.3. 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>C	p.Met44Leu	missense	Exon 2 of 11	NP_001341859.1	Q13546-1
	RIPK1	NM_001317061.3		c.-474A>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 13	NP_001303990.1
	RIPK1	NM_001354932.2		c.-474A>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	NP_001341861.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK1	ENST00000259808.9	TSL:5 MANE Select	c.130A>C	p.Met44Leu	missense	Exon 2 of 11	ENSP00000259808.3	Q13546-1
	RIPK1	ENST00000380409.3	TSL:1	c.130A>C	p.Met44Leu	missense	Exon 2 of 10	ENSP00000369773.3	Q13546-2
	RIPK1	ENST00000967583.1		c.130A>C	p.Met44Leu	missense	Exon 2 of 12	ENSP00000637642.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1435778 Hom.: 0 Cov.: 34 AF XY: 0.00000280 AC XY: 2 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: 0.0000233 AC: 2 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

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.3
DANN	Benign	0.37
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.94	N
PhyloP100		0.78
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.55		Gain of catalytic residue at M44 (P = 0.0388)
MVP		0.47
MPC		0.20
ClinPred		0.042	T
GERP RS		2.7
Varity_R		0.11
gMVP		0.44
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs1393554291; hg19: chr6-3077187;