17-5500619-T-C

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

Scores

1
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.80

Publications

0 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LOC728392NM_001162371.3 linkc.338A>G p.Tyr113Cys missense_variant Exon 1 of 2 ENST00000568641.2 NP_001155843.1 A0A494C1I1
LOC124900388XM_047437232.1 linkc.-296A>G 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 2 XP_047293188.1
LOC124900388XM_047437232.1 linkc.-296A>G 5_prime_UTR_variant Exon 1 of 2 XP_047293188.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ENSG00000286190ENST00000568641.2 linkc.338A>G p.Tyr113Cys missense_variant Exon 1 of 2 1 NM_001162371.3 ENSP00000499042.1 A0A494C1I1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000849
AC:
10
AN:
117792
AF XY:
0.000142
show subpopulations
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
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.487
Heterozygous variant carriers
0
3
5
8
10
13
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 05, 2021
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.338A>G (p.Y113C) alteration is located in exon 1 (coding exon 1) of the LOC728392 gene. This alteration results from a A to G substitution at nucleotide position 338, causing the tyrosine (Y) at amino acid position 113 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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

Publications

Other links and lift over

dbSNP: rs770131004; hg19: chr17-5403939; API