rs7765221

Variant names:

• chr6-3108054-A-G
• rs7765221
• NM_001354930.2:c.1576+2003A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001354930.2(RIPK1):​c.1576+2003A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.939 in 151,614 control chromosomes in the GnomAD database, including 66,956 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.94 (66956 hom., cov: 26)
• Consequence: RIPK1 NM_001354930.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0710
• Publications: 6 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

LOC107986556 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

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.1576+2003A>G		intron	N/A	NP_001341859.1	Q13546-1
	RIPK1	NM_003804.6		c.1576+2003A>G		intron	N/A	NP_003795.2	Q13546-1
	RIPK1	NM_001354931.2		c.1438+2003A>G		intron	N/A	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.1576+2003A>G		intron	N/A	ENSP00000259808.3	Q13546-1
	RIPK1	ENST00000380409.3	TSL:1	c.1438+2003A>G		intron	N/A	ENSP00000369773.3	Q13546-2
	RIPK1	ENST00000967583.1		c.1639+2003A>G		intron	N/A	ENSP00000637642.1

Frequencies

GnomAD3 genomes AF: 0.939 AC: 142289 AN: 151496 Hom.: 66898 Cov.: 26

Gnomad AFR AF: 0.981

Gnomad AMI AF: 0.892

Gnomad AMR AF: 0.931

Gnomad ASJ AF: 0.882

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.932

Gnomad FIN AF: 0.966

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.916

Gnomad OTH AF: 0.930

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.939 AC: 142406 AN: 151614 Hom.: 66956 Cov.: 26 AF XY: 0.942 AC XY: 69741 AN XY: 74032

African (AFR) AF: 0.981 AC: 40597 AN: 41372

American (AMR) AF: 0.931 AC: 14106 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.882 AC: 3063 AN: 3472

East Asian (EAS) AF: 0.939 AC: 4759 AN: 5070

South Asian (SAS) AF: 0.932 AC: 4485 AN: 4810

European-Finnish (FIN) AF: 0.966 AC: 10115 AN: 10476

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.916 AC: 62263 AN: 67960

Other (OTH) AF: 0.927 AC: 1949 AN: 2102

Alfa AF: 0.926 Hom.: 53744

Bravo AF: 0.937

Asia WGS AF: 0.945 AC: 3284 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.4
DANN	Benign	0.81
PhyloP100		-0.071
Mutation Taster		=100/0	polymorphism (auto)

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: rs7765221; hg19: chr6-3108288;