6-3110950-T-C

Variant names:

• chr6-3110950-T-C
• rs760790406
• NM_001354930.2:c.1724T>C
• RIPK1 p.Ile575Thr

Variant summary

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

The NM_001354930.2(RIPK1):​c.1724T>C​(p.Ile575Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I575V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RIPK1 NM_001354930.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52
• Publications: 0 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, ClinGen
• autoinflammation with episodic fever and lymphadenopathy

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC107986556 (HGNC:):

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=0.19250047).

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.1724T>C	p.Ile575Thr	missense	Exon 10 of 11	NP_001341859.1	Q13546-1
	RIPK1	NM_003804.6		c.1724T>C	p.Ile575Thr	missense	Exon 10 of 11	NP_003795.2	Q13546-1
	RIPK1	NM_001354931.2		c.1586T>C	p.Ile529Thr	missense	Exon 9 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.1724T>C	p.Ile575Thr	missense	Exon 10 of 11	ENSP00000259808.3	Q13546-1
	RIPK1	ENST00000380409.3	TSL:1	c.1586T>C	p.Ile529Thr	missense	Exon 9 of 10	ENSP00000369773.3	Q13546-2
	RIPK1	ENST00000967583.1		c.1787T>C	p.Ile596Thr	missense	Exon 11 of 12	ENSP00000637642.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457760 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725312

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000300 AC: 1 AN: 33314

American (AMR) AF: 0.00 AC: 0 AN: 43980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 85396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110256

Other (OTH) AF: 0.00 AC: 0 AN: 60216

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.057
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Varity_R		0.25
gMVP		0.63
Mutation Taster		=60/40	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs760790406;

hg19: chr6-3111184;