rs4713951

Variant names:

• chr6-36295214-C-T
• rs4713951
• NM_001374623.1:c.715-150C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001374623.1(PNPLA1):​c.715-150C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 722,284 control chromosomes in the GnomAD database, including 73,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.43 (14491 hom., cov: 32)
  • Exomes 𝑓: 0.45 (59325 hom.)
• Consequence: PNPLA1 NM_001374623.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.63
• Publications: 14 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 6-36295214-C-T is Benign according to our data. Variant chr6-36295214-C-T is described in ClinVar as Benign. ClinVar VariationId is 1249564.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA1	NM_001374623.1	c.715-150C>T		intron_variant	Intron 4 of 8	ENST00000636260.2	NP_001361552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA1	ENST00000636260.2	c.715-150C>T		intron_variant	Intron 4 of 8	5	NM_001374623.1	ENSP00000490785.2
PNPLA1	ENST00000457797.5	c.718-150C>T		intron_variant	Intron 4 of 7	1		ENSP00000391868.1

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65387 AN: 151962 Hom.: 14469 Cov.: 32

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.410

GnomAD4 exome AF: 0.447 AC: 254670 AN: 570204 Hom.: 59325 AF XY: 0.445 AC XY: 133858 AN XY: 301034

African (AFR) AF: 0.364 AC: 5785 AN: 15906

American (AMR) AF: 0.625 AC: 19706 AN: 31514

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 5719 AN: 16708

East Asian (EAS) AF: 0.624 AC: 19596 AN: 31388

South Asian (SAS) AF: 0.461 AC: 25619 AN: 55588

European-Finnish (FIN) AF: 0.488 AC: 19979 AN: 40906

Middle Eastern (MID) AF: 0.412 AC: 984 AN: 2386

European-Non Finnish (NFE) AF: 0.418 AC: 144551 AN: 345682

Other (OTH) AF: 0.423 AC: 12731 AN: 30126

GnomAD4 genome AF: 0.430 AC: 65445 AN: 152080 Hom.: 14491 Cov.: 32 AF XY: 0.438 AC XY: 32551 AN XY: 74328

African (AFR) AF: 0.373 AC: 15470 AN: 41470

American (AMR) AF: 0.525 AC: 8022 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1157 AN: 3470

East Asian (EAS) AF: 0.600 AC: 3098 AN: 5166

South Asian (SAS) AF: 0.457 AC: 2204 AN: 4828

European-Finnish (FIN) AF: 0.508 AC: 5367 AN: 10564

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.424 AC: 28818 AN: 67976

Other (OTH) AF: 0.404 AC: 855 AN: 2116

Alfa AF: 0.427 Hom.: 32198

Bravo AF: 0.430

Asia WGS AF: 0.465 AC: 1616 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

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	-0.96
CADD	Benign	0.032
DANN	Benign	0.76
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4713951; hg19: chr6-36262991;