6-36306371-T-A

Position:

chr6-36306371-T-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2

The NM_001374623.1(PNPLA1):c.1464T>A(p.Tyr488*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 1,610,946 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.011 ( 15 hom., cov: 31)

Exomes 𝑓: 0.016 ( 228 hom. )

Consequence

PNPLA1
NM_001374623.1 stop_gained

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -5.48

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]

PNPLA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 6-36306371-T-A is Benign according to our data. Variant chr6-36306371-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 403331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1696/152274) while in subpopulation NFE AF= 0.018 (1224/68026). AF 95% confidence interval is 0.0172. There are 15 homozygotes in gnomad4. There are 776 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA1	NM_001374623.1 linkuse as main transcript	c.1464T>A	p.Tyr488*	stop_gained	7/9	ENST00000636260.2	NP_001361552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA1	ENST00000636260.2 linkuse as main transcript	c.1464T>A	p.Tyr488*	stop_gained	7/9	5	NM_001374623.1	ENSP00000490785.2		A0A1B0GW56
PNPLA1	ENST00000457797.5 linkuse as main transcript	c.1467T>A	p.Tyr489*	stop_gained	7/8	1		ENSP00000391868.1		A0A0C4DG24

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1697

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0138

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0180

Gnomad OTH

AF:

0.0172

GnomAD3 exomes

AF:

0.0116

AC:

2887

AN:

247820

Hom.:

AF XY:

0.0121

AC XY:

1621

AN XY:

134020

show subpopulations

Gnomad AFR exome

AF:

0.00236

Gnomad AMR exome

AF:

0.00997

Gnomad ASJ exome

AF:

0.0162

Gnomad EAS exome

AF:

0.00139

Gnomad SAS exome

AF:

0.00335

Gnomad FIN exome

AF:

0.00440

Gnomad NFE exome

AF:

0.0182

Gnomad OTH exome

AF:

0.0133

GnomAD4 exome

AF:

0.0159

AC:

23196

AN:

1458672

Hom.:

228

Cov.:

AF XY:

0.0155

AC XY:

11224

AN XY:

725726

show subpopulations

Gnomad4 AFR exome

AF:

0.00262

Gnomad4 AMR exome

AF:

0.0107

Gnomad4 ASJ exome

AF:

0.0161

Gnomad4 EAS exome

AF:

0.000833

Gnomad4 SAS exome

AF:

0.00336

Gnomad4 FIN exome

AF:

0.00405

Gnomad4 NFE exome

AF:

0.0187

Gnomad4 OTH exome

AF:

0.0146

GnomAD4 genome

AF:

0.0111

AC:

1696

AN:

152274

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

776

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00284

Gnomad4 AMR

AF:

0.0138

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00386

Gnomad4 NFE

AF:

0.0180

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.0161

Hom.:

Bravo

AF:

0.0123

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0148

AC:

127

ExAC

AF:

0.0114

AC:

1379

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0200

EpiControl

AF:

0.0201

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (EUR): 127/8600= 1.47% -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: PNPLA1 c.1464T>A (p.Tyr488X) results in a premature termination codon at the end of the penultimate exon (exon 7), predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. To our knowledge, no truncations or pathogenic variants downstream of this position have been cited in online databases (ClinVar, HGMD, LOVD). The variant allele was found at a frequency of 0.012 in 247820 control chromosomes in the gnomAD database, including 33 homozygotes. The observed variant frequency is approximately 27-fold of the estimated maximal expected allele frequency for a pathogenic variant in PNPLA1 causing Lamellar Ichthyosis phenotype (0.00043), strongly suggesting that the variant is benign. c.1464T>A has been reported in the literature in a homozygous individual affected with autism spectrum disorder (Lim_2013) and it was also reported in the heterozygous state in families affected with ichthyosis but it was concluded not to be causative of the disease (Vahidnezhad_2017). In addition, the variant has been reported in the literature in multiple homozygous unaffected individuals (Lim_2013, Abouelhoda_2016, John_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	PNPLA1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive congenital ichthyosis 10

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 13, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Benign

0.88

Eigen

Benign

-0.70

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0060

Vest4

0.26

GERP RS

-8.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over