6-36293081-C-T

Variant names:

• chr6-36293081-C-T
• rs2239795
• NM_001374623.1:c.459C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001374623.1(PNPLA1):​c.459C>T​(p.Phe153Phe) 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
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive congenital ichthyosis 10

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 257572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PNPLA1	NM_001374623.1	c.459C>T	p.Phe153Phe	synonymous_variant	Exon 3 of 9	ENST00000636260.2	NP_001361552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA1	ENST00000636260.2	c.459C>T	p.Phe153Phe	synonymous_variant	Exon 3 of 9	5	NM_001374623.1	ENSP00000490785.2
PNPLA1	ENST00000457797.5	c.462C>T	p.Phe154Phe	synonymous_variant	Exon 3 of 8	1		ENSP00000391868.1

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

GnomAD2 exomes AF: 0.371 AC: 93102 AN: 250940 AF XY: 0.372

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 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

African (AFR) AF: 0.536 AC: 17931 AN: 33444

American (AMR) AF: 0.263 AC: 11750 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 12648 AN: 26122

East Asian (EAS) AF: 0.308 AC: 12242 AN: 39684

South Asian (SAS) AF: 0.337 AC: 29082 AN: 86212

European-Finnish (FIN) AF: 0.378 AC: 20178 AN: 53388

Middle Eastern (MID) AF: 0.419 AC: 2414 AN: 5764

European-Non Finnish (NFE) AF: 0.382 AC: 424078 AN: 1111268

Other (OTH) AF: 0.398 AC: 24000 AN: 60364

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

African (AFR) AF: 0.525 AC: 21730 AN: 41390

American (AMR) AF: 0.358 AC: 5462 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 1679 AN: 3464

East Asian (EAS) AF: 0.338 AC: 1741 AN: 5156

South Asian (SAS) AF: 0.345 AC: 1655 AN: 4804

European-Finnish (FIN) AF: 0.364 AC: 3843 AN: 10552

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26555 AN: 67914

Other (OTH) AF: 0.450 AC: 943 AN: 2094

Alfa AF: 0.404 Hom.: 20636

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

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive congenital ichthyosis 10 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	5.0
DANN	Benign	0.74
PhyloP100		-1.1
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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