6-36270608-C-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.149C>A​(p.Ala50Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,366 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 0.0000066 ( 0 hom., cov: 32)

Consequence

PNPLA1
NM_001374623.1 missense

Scores

2
7
10

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.29
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]

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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 0 benign, 4 uncertain in NM_001374623.1
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.914
PP5
Variant 6-36270608-C-A is Pathogenic according to our data. Variant chr6-36270608-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 633797.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.149C>A p.Ala50Glu missense_variant 1/9 ENST00000636260.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PNPLA1ENST00000636260.2 linkuse as main transcriptc.149C>A p.Ala50Glu missense_variant 1/95 NM_001374623.1 A2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152248
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:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000651
AC:
1
AN:
153556
Hom.:
0
AF XY:
0.0000123
AC XY:
1
AN XY:
81622
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:
0.0000439
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
AF:
0.00000656
AC:
1
AN:
152366
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74506
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:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000402
AC:
1

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 testingUitto Lab, Thomas Jefferson UniversityJun 08, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Uncertain
0.095
D
BayesDel_noAF
Uncertain
0.030
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.30
.;T
Eigen
Benign
0.039
Eigen_PC
Benign
-0.16
FATHMM_MKL
Benign
0.028
N
LIST_S2
Benign
0.71
T;T
M_CAP
Benign
0.074
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Benign
-0.57
T
MutationAssessor
Uncertain
2.7
.;M
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-1.4
N;N
REVEL
Uncertain
0.53
Sift
Uncertain
0.014
D;D
Sift4G
Benign
0.14
T;T
Polyphen
1.0
.;D
Vest4
0.77
MutPred
0.83
Gain of disorder (P = 0.0227);Gain of disorder (P = 0.0227);
MVP
0.83
MPC
0.81
ClinPred
0.71
D
GERP RS
2.5
Varity_R
0.54

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: rs533584507; hg19: chr6-36238385; API