6-36270637-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_001374623.1(PNPLA1):​c.178G>A​(p.Ala60Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000148 in 1,551,122 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 Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PNPLA1
NM_001374623.1 missense

Scores

1
10
8

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.82
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 8 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001374623.1
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.857
PP5
Variant 6-36270637-G-A is Pathogenic according to our data. Variant chr6-36270637-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1705673.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PNPLA1NM_001374623.1 linkuse as main transcriptc.178G>A p.Ala60Thr missense_variant 1/9 ENST00000636260.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PNPLA1ENST00000636260.2 linkuse as main transcriptc.178G>A p.Ala60Thr missense_variant 1/95 NM_001374623.1 A2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152248
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000197
AC:
3
AN:
152376
Hom.:
0
AF XY:
0.0000123
AC XY:
1
AN XY:
81106
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000515
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000150
AC:
21
AN:
1398874
Hom.:
0
Cov.:
32
AF XY:
0.0000130
AC XY:
9
AN XY:
689982
show subpopulations
Gnomad4 AFR exome
AF:
0.0000317
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:
0.0000176
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152248
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000189

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 10 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testing3billionSep 01, 2022The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.61; 3Cnet: NA). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Uncertain
0.072
D
BayesDel_noAF
Uncertain
-0.030
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.10
.;T
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.69
T;T
M_CAP
Uncertain
0.095
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Benign
1.6
.;L
MutationTaster
Benign
0.77
D;D;D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-1.1
N;N
REVEL
Uncertain
0.61
Sift
Benign
0.12
T;T
Sift4G
Benign
0.13
T;T
Polyphen
1.0
.;D
Vest4
0.69
MutPred
0.66
Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP
0.78
MPC
0.77
ClinPred
0.91
D
GERP RS
4.5
Varity_R
0.14

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs1029691431; hg19: chr6-36238414; API