6-36270551-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001374623.1(PNPLA1):​c.92C>A​(p.Ala31Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 1,551,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A31V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PNPLA1
NM_001374623.1 missense

Scores

5
8
6

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.0600
Variant links:
Genes affected
PNPLA1 (HGNC:21246): (patatin like phospholipase domain containing 1) The protein encoded by this gene belongs to the patatin-like phospholipase (PNPLA) family, which is characterized by the presence of a highly conserved patatin domain. PNPLA family members have diverse lipolytic and acyltransferase activities, and are key elements in lipid metabolism. While other members of this family have been well characterized, the function of this gene remained an enigma. However, recent studies show that this gene is expressed in the skin epidermal keratinocytes, and has a role in glycerophospholipid metabolism in the cutaneous barrier. Consistent with these observations, mutations in this gene are associated with ichthyosis in human (autosomal recessive congenital ichthyoses, ARCI) and dog. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.956
PP5
Variant 6-36270551-C-A is Pathogenic according to our data. Variant chr6-36270551-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 684637.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PNPLA1NM_001374623.1 linkuse as main transcriptc.92C>A p.Ala31Asp missense_variant 1/9 ENST00000636260.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PNPLA1ENST00000636260.2 linkuse as main transcriptc.92C>A p.Ala31Asp missense_variant 1/95 NM_001374623.1 A2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152252
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000214
AC:
3
AN:
1399260
Hom.:
0
Cov.:
32
AF XY:
0.00000290
AC XY:
2
AN XY:
690142
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000278
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152252
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74378
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Congenital ichthyosiform erythroderma Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyYale Center for Mendelian Genomics, Yale UniversityJun 07, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.55
.;D
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.43
FATHMM_MKL
Benign
0.045
N
LIST_S2
Benign
0.71
T;T
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Benign
-0.37
T
MutationAssessor
Uncertain
2.7
.;M
MutationTaster
Benign
1.0
D;D;N;N
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-4.0
D;D
REVEL
Pathogenic
0.65
Sift
Uncertain
0.0050
D;D
Sift4G
Uncertain
0.010
D;D
Polyphen
1.0
.;D
Vest4
0.91
MutPred
0.82
Loss of catalytic residue at A31 (P = 0.1002);Loss of catalytic residue at A31 (P = 0.1002);
MVP
0.83
MPC
0.96
ClinPred
0.97
D
GERP RS
0.33
Varity_R
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1231123861; hg19: chr6-36238328; API