rs6920337

Variant names:

• chr6-3073678-G-A
• rs6920337
• NM_001354930.2:c.-60-3086G>A

Variant summary

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

The ENST00000259808.9(RIPK1):​c.-60-3086G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,092 control chromosomes in the GnomAD database, including 3,436 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 0.19 (3436 hom., cov: 32)
• Consequence: RIPK1 ENST00000259808.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.636
• Publications: 10 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000259808.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK1	NM_001354930.2	MANE Select	c.-60-3086G>A		intron	N/A	NP_001341859.1
	RIPK1	NM_001317061.3		c.-788G>A		5_prime_UTR	Exon 2 of 13	NP_001303990.1
	RIPK1	NM_003804.6		c.-60-3086G>A		intron	N/A	NP_003795.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK1	ENST00000259808.9	TSL:5 MANE Select	c.-60-3086G>A		intron	N/A	ENSP00000259808.3
	RIPK1	ENST00000380409.3	TSL:1	c.-60-3086G>A		intron	N/A	ENSP00000369773.3
	RIPK1	ENST00000676965.1		n.-185G>A		non_coding_transcript_exon	Exon 1 of 10	ENSP00000503708.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29607 AN: 151974 Hom.: 3436 Cov.: 32

Gnomad AFR AF: 0.0615

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.224

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

GnomAD4 genome AF: 0.195 AC: 29609 AN: 152092 Hom.: 3436 Cov.: 32 AF XY: 0.196 AC XY: 14559 AN XY: 74342

African (AFR) AF: 0.0613 AC: 2546 AN: 41508

American (AMR) AF: 0.202 AC: 3084 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 646 AN: 3470

East Asian (EAS) AF: 0.303 AC: 1567 AN: 5174

South Asian (SAS) AF: 0.225 AC: 1082 AN: 4814

European-Finnish (FIN) AF: 0.245 AC: 2588 AN: 10550

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17421 AN: 67976

Other (OTH) AF: 0.226 AC: 476 AN: 2104

Alfa AF: 0.228 Hom.: 4484

Bravo AF: 0.185

Asia WGS AF: 0.271 AC: 940 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.5
DANN	Benign	0.39
PhyloP100		0.64
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: rs6920337; hg19: chr6-3073912;