rs2239795

chr6-36293081-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001374623.1(PNPLA1):c.459C>T(p.Phe153=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,612,774 control chromosomes in the GnomAD database, including 121,341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14009 hom., cov: 31)
  • Exomes 𝑓: 0.38 (107332 hom.)
• Consequence: PNPLA1 NM_001374623.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.09

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 6-36293081-C-T is Benign according to our data. Variant chr6-36293081-C-T is described in ClinVar as [Benign]. Clinvar id is 257572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-36293081-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA1	NM_001374623.1	c.459C>T	p.Phe153=	synonymous_variant	3/9	ENST00000636260.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA1	ENST00000636260.2	c.459C>T	p.Phe153=	synonymous_variant	3/9	5	NM_001374623.1	A2

Frequencies

GnomAD3 genomes AF: 0.422 AC: 63951 AN: 151720 Hom.: 13992 Cov.: 31

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.449

GnomAD3 exomes AF: 0.371 AC: 93102 AN: 250940 Hom.: 18226 AF XY: 0.372 AC XY: 50490 AN XY: 135588

Gnomad AFR exome AF: 0.524

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.482

Gnomad EAS exome AF: 0.354

Gnomad SAS exome AF: 0.335

Gnomad FIN exome AF: 0.374

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.391

GnomAD4 exome AF: 0.379 AC: 554323 AN: 1460936 Hom.: 107332 Cov.: 42 AF XY: 0.380 AC XY: 276218 AN XY: 726798

Gnomad4 AFR exome AF: 0.536

Gnomad4 AMR exome AF: 0.263

Gnomad4 ASJ exome AF: 0.484

Gnomad4 EAS exome AF: 0.308

Gnomad4 SAS exome AF: 0.337

Gnomad4 FIN exome AF: 0.378

Gnomad4 NFE exome AF: 0.382

Gnomad4 OTH exome AF: 0.398

GnomAD4 genome AF: 0.422 AC: 64002 AN: 151838 Hom.: 14009 Cov.: 31 AF XY: 0.417 AC XY: 30919 AN XY: 74208

Gnomad4 AFR AF: 0.525

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.485

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.345

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.391

Gnomad4 OTH AF: 0.450

Alfa AF: 0.403 Hom.: 16657

Bravo AF: 0.424

Asia WGS AF: 0.408 AC: 1421 AN: 3478

EpiCase AF: 0.400

EpiControl AF: 0.405

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Autosomal recessive congenital ichthyosis 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	5.0
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2239795; hg19: chr6-36260858; COSMIC: COSV57233158;