17-5500619-T-C

Variant names:

• chr17-5500619-T-C
• rs770131004
• NM_001162371.3:c.338A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001162371.3(LOC728392):​c.338A>G​(p.Tyr113Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000351 in 1,112,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: LOC728392 NM_001162371.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80
• Publications: 0 publications found

Genes affected

LOC728392 (HGNC:0):

LOC124900388 (HGNC:):

ENSG00000286190 (HGNC:58752):

NLRP1 (HGNC:14374): (NLR family pyrin domain containing 1) This gene encodes a member of the Ced-4 family of apoptosis proteins. Ced-family members contain a caspase recruitment domain (CARD) and are known to be key mediators of programmed cell death. The encoded protein contains a distinct N-terminal pyrin-like motif, which is possibly involved in protein-protein interactions. This protein interacts strongly with caspase 2 and weakly with caspase 9. Overexpression of this gene was demonstrated to induce apoptosis in cells. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

NLRP1 Gene-Disease associations (from GenCC):

• autoinflammation with arthritis and dyskeratosis

  Inheritance: AR, SD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome

  Inheritance: SD, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001162371.3. 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
	LOC728392	NM_001162371.3	MANE Select	c.338A>G	p.Tyr113Cys	missense	Exon 1 of 2	NP_001155843.1	A0A494C1I1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000286190	ENST00000568641.2	TSL:1 MANE Select	c.338A>G	p.Tyr113Cys	missense	Exon 1 of 2	ENSP00000499042.1	A0A494C1I1
	ENSG00000286190	ENST00000956689.1		c.338A>G	p.Tyr113Cys	missense	Exon 1 of 2	ENSP00000626748.1
	NLRP1	ENST00000699801.1		c.188-669A>G		intron	N/A	ENSP00000514604.1	A0A8V8TQK4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000849 AC: 10 AN: 117792 AF XY: 0.000142

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000351 AC: 39 AN: 1112558 Hom.: 0 Cov.: 30 AF XY: 0.0000569 AC XY: 31 AN XY: 544440

African (AFR) AF: 0.0000476 AC: 1 AN: 21026

American (AMR) AF: 0.00 AC: 0 AN: 22218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15062

East Asian (EAS) AF: 0.00 AC: 0 AN: 7666

South Asian (SAS) AF: 0.000540 AC: 38 AN: 70404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4268

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 903838

Other (OTH) AF: 0.00 AC: 0 AN: 39928

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Benign	0.80
PhyloP100		1.8
PromoterAI		-0.017	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770131004; hg19: chr17-5403939;