rs1057519492

Variant names:

• chr17-5583798-C-A
• rs1057519492
• NM_033004.4:c.160G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-5583798-C-A
• chr17-5583798-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_033004.4(NLRP1):​c.160G>T​(p.Ala54Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,405,058 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict 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. A54T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NLRP1 NM_033004.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.55
• Publications: 0 publications found

Genes affected

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):

• corneal intraepithelial dyskeratosis-palmoplantar hyperkeratosis-laryngeal dyskeratosis syndrome

  Inheritance: AD, SD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• autoinflammation with arthritis and dyskeratosis

  Inheritance: AR, SD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-5583798-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 375413.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLRP1	NM_033004.4	c.160G>T	p.Ala54Ser	missense_variant	Exon 1 of 17	ENST00000572272.6	NP_127497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLRP1	ENST00000572272.6	c.160G>T	p.Ala54Ser	missense_variant	Exon 1 of 17	1	NM_033004.4	ENSP00000460475.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1405058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 693658

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

African (AFR) AF: 0.00 AC: 0 AN: 31974

American (AMR) AF: 0.00 AC: 0 AN: 36590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25304

East Asian (EAS) AF: 0.00 AC: 0 AN: 36206

South Asian (SAS) AF: 0.00 AC: 0 AN: 79836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1081742

Other (OTH) AF: 0.00 AC: 0 AN: 58200

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0083	.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.070
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.80	.;T;.;.;.;.;T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.80	T
PhyloP100		1.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N;.;.;N;.;N;.;.;.;N
REVEL	Benign	0.25
Sift	Uncertain	0.0090	D;.;.;D;.;D;.;.;.;D
Sift4G	Uncertain	0.030	D;D;.;D;D;D;D;D;D;D
Polyphen		0.94, 1.0, 1.0	.;.;P;P;D;D;D;D;D;P
Vest4		0.28
MutPred		0.73		Gain of disorder (P = 0.0256);Gain of disorder (P = 0.0256);Gain of disorder (P = 0.0256);Gain of disorder (P = 0.0256);Gain of disorder (P = 0.0256);Gain of disorder (P = 0.0256);Gain of disorder (P = 0.0256);Gain of disorder (P = 0.0256);Gain of disorder (P = 0.0256);Gain of disorder (P = 0.0256);
MVP		0.75
MPC		0.73
ClinPred		0.92	D
GERP RS		2.5
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.58
Mutation Taster		=74/26	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

Other links and lift over

dbSNP: rs1057519492; hg19: chr17-5487118;