rs6903663

Variant names:

• chr6-36262887-A-C
• rs6903663
• ENST00000312917.9:c.-81+19626A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000312917.9(PNPLA1):​c.-81+19626A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 152,124 control chromosomes in the GnomAD database, including 14,080 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (14080 hom., cov: 33)
• Consequence: PNPLA1 ENST00000312917.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.851
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000312917.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA1	NM_001145716.2		c.-81+19626A>C		intron	N/A	NP_001139188.1
	PNPLA1	NM_173676.2		c.-81+19626A>C		intron	N/A	NP_775947.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA1	ENST00000312917.9	TSL:1	c.-81+19626A>C		intron	N/A	ENSP00000321116.5
	PNPLA1	ENST00000388715.7	TSL:1	c.-81+19626A>C		intron	N/A	ENSP00000373367.3

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63870 AN: 152006 Hom.: 14060 Cov.: 33

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.398

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.420 AC: 63936 AN: 152124 Hom.: 14080 Cov.: 33 AF XY: 0.425 AC XY: 31609 AN XY: 74374

African (AFR) AF: 0.547 AC: 22698 AN: 41490

American (AMR) AF: 0.391 AC: 5982 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 1382 AN: 3472

East Asian (EAS) AF: 0.379 AC: 1961 AN: 5174

South Asian (SAS) AF: 0.589 AC: 2844 AN: 4832

European-Finnish (FIN) AF: 0.385 AC: 4072 AN: 10588

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.348 AC: 23669 AN: 67970

Other (OTH) AF: 0.393 AC: 829 AN: 2112

Alfa AF: 0.367 Hom.: 4977

Bravo AF: 0.420

Asia WGS AF: 0.448 AC: 1555 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.71
PhyloP100		-0.85
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: rs6903663; hg19: chr6-36230664;