NM_001354930.2:c.71A>C

Variant names:

• chr6-3076894-A-C
• rs375750553
• NM_001354930.2:c.71A>C

Variant summary

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

The NM_001354930.2(RIPK1):​c.71A>C​(p.Asp24Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,459,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D24V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: RIPK1 NM_001354930.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60
• 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.

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.71A>C	p.Asp24Ala	missense	Exon 2 of 11	NP_001341859.1	Q13546-1
	RIPK1	NM_003804.6		c.71A>C	p.Asp24Ala	missense	Exon 2 of 11	NP_003795.2	Q13546-1
	RIPK1	NM_001354931.2		c.71A>C	p.Asp24Ala	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.71A>C	p.Asp24Ala	missense	Exon 2 of 11	ENSP00000259808.3	Q13546-1
	RIPK1	ENST00000380409.3	TSL:1	c.71A>C	p.Asp24Ala	missense	Exon 2 of 10	ENSP00000369773.3	Q13546-2
	RIPK1	ENST00000967583.1		c.71A>C	p.Asp24Ala	missense	Exon 2 of 12	ENSP00000637642.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459612 Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4 AN XY: 726306

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1110056

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 27

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	0.18
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.87	N
PhyloP100		3.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.011	D
Sift4G	Benign	0.072	T
Polyphen		0.98	D
Vest4		0.39
MutPred		0.64		Loss of sheet (P = 0.0817)
MVP		0.81
MPC		0.59
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.45
gMVP		0.80
Mutation Taster		=24/76	disease causing

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: rs375750553; hg19: chr6-3077128;