6-36270635-C-T

Variant summary

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

The NM_001374623.1(PNPLA1):​c.176C>T​(p.Ala59Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. A59T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PNPLA1
NM_001374623.1 missense

Scores

7
10
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.40
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 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.965
PP5
Variant 6-36270635-C-T is Pathogenic according to our data. Variant chr6-36270635-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39562.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.176C>T p.Ala59Val missense_variant 1/9 ENST00000636260.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PNPLA1ENST00000636260.2 linkuse as main transcriptc.176C>T p.Ala59Val missense_variant 1/95 NM_001374623.1 A2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Autosomal recessive congenital ichthyosis 10 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 15, 2012- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.52
.;D
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Benign
0.80
T;T
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Uncertain
0.69
D
MutationAssessor
Pathogenic
3.0
.;M
MutationTaster
Benign
0.74
D;D;D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.1
D;D
REVEL
Pathogenic
0.77
Sift
Uncertain
0.018
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
.;D
Vest4
0.95
MutPred
0.79
Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MPC
0.78
ClinPred
0.98
D
GERP RS
4.5
Varity_R
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs1561853847; hg19: chr6-36238412; API