6-3075319-A-G

Variant names:

• chr6-3075319-A-G
• rs2326173
• NM_001354930.2:c.-60-1445A>G

Variant summary

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

The NM_003804.6(RIPK1):​c.-60-1445A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 151,958 control chromosomes in the GnomAD database, including 27,723 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 0.60 (27723 hom., cov: 31)
• Consequence: RIPK1 NM_003804.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.75
• Publications: 13 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003804.6. 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.-60-1445A>G		intron	N/A	NP_001341859.1
	RIPK1	NM_003804.6		c.-60-1445A>G		intron	N/A	NP_003795.2
	RIPK1	NM_001354931.2		c.-60-1445A>G		intron	N/A	NP_001341860.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK1	ENST00000259808.9	TSL:5 MANE Select	c.-60-1445A>G		intron	N/A	ENSP00000259808.3
	RIPK1	ENST00000380409.3	TSL:1	c.-60-1445A>G		intron	N/A	ENSP00000369773.3
	RIPK1	ENST00000967583.1		c.-60-1445A>G		intron	N/A	ENSP00000637642.1

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90664 AN: 151840 Hom.: 27717 Cov.: 31

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.732

Gnomad AMR AF: 0.645

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.596

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

GnomAD4 genome AF: 0.597 AC: 90696 AN: 151958 Hom.: 27723 Cov.: 31 AF XY: 0.594 AC XY: 44064 AN XY: 74236

African (AFR) AF: 0.480 AC: 19872 AN: 41430

American (AMR) AF: 0.645 AC: 9841 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2532 AN: 3470

East Asian (EAS) AF: 0.426 AC: 2199 AN: 5162

South Asian (SAS) AF: 0.606 AC: 2922 AN: 4818

European-Finnish (FIN) AF: 0.616 AC: 6485 AN: 10528

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44754 AN: 67970

Other (OTH) AF: 0.592 AC: 1252 AN: 2116

Alfa AF: 0.643 Hom.: 137020

Bravo AF: 0.596

Asia WGS AF: 0.501 AC: 1744 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		1.7
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: rs2326173; hg19: chr6-3075553;