6-36270545-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001374623.1(PNPLA1):​c.86C>T​(p.Ala29Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,551,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A29A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

PNPLA1
NM_001374623.1 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.11
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11572862).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PNPLA1NM_001374623.1 linkuse as main transcriptc.86C>T p.Ala29Val missense_variant 1/9 ENST00000636260.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PNPLA1ENST00000636260.2 linkuse as main transcriptc.86C>T p.Ala29Val missense_variant 1/95 NM_001374623.1 A2

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152234
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000578
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000517
AC:
8
AN:
154630
Hom.:
0
AF XY:
0.0000608
AC XY:
5
AN XY:
82198
show subpopulations
Gnomad AFR exome
AF:
0.000128
Gnomad AMR exome
AF:
0.0000405
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000368
Gnomad SAS exome
AF:
0.0000878
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000264
AC:
37
AN:
1399246
Hom.:
0
Cov.:
32
AF XY:
0.0000304
AC XY:
21
AN XY:
690142
show subpopulations
Gnomad4 AFR exome
AF:
0.000190
Gnomad4 AMR exome
AF:
0.0000840
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000560
Gnomad4 SAS exome
AF:
0.0000631
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000176
Gnomad4 OTH exome
AF:
0.0000345
GnomAD4 genome
AF:
0.0000853
AC:
13
AN:
152352
Hom.:
0
Cov.:
32
AF XY:
0.000134
AC XY:
10
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000579
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.000110
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000404
AC:
1
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 07, 2024The c.86C>T (p.A29V) alteration is located in exon 1 (coding exon 1) of the PNPLA1 gene. This alteration results from a C to T substitution at nucleotide position 86, causing the alanine (A) at amino acid position 29 to be replaced by a valine (V). 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
Benign
0.22
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
21
DANN
Benign
0.77
DEOGEN2
Benign
0.033
.;T
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.30
N
LIST_S2
Benign
0.72
T;T
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
-0.33
.;N
MutationTaster
Benign
1.0
D;D;N;N
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
2.0
N;N
REVEL
Benign
0.25
Sift
Benign
0.88
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.65
.;P
Vest4
0.28
MutPred
0.47
Loss of catalytic residue at A29 (P = 0.2543);Loss of catalytic residue at A29 (P = 0.2543);
MVP
0.78
MPC
0.46
ClinPred
0.033
T
GERP RS
3.3
Varity_R
0.053

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.17
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: rs560901405; hg19: chr6-36238322; COSMIC: COSV57232803; API