chr6-36285433-T-C

Variant names:

• chr6-36285433-T-C
• rs1467912
• NM_001374623.1:c.206-5887T>C

Variant summary

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

The NM_001374623.1(PNPLA1):​c.206-5887T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 152,080 control chromosomes in the GnomAD database, including 31,677 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 0.65 (31677 hom., cov: 32)
• Consequence: PNPLA1 NM_001374623.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.575
• Publications: 1 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374623.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA1	NM_001374623.1	MANE Select	c.206-5887T>C		intron	N/A	NP_001361552.1	A0A1B0GW56
	PNPLA1	NM_001145717.1		c.206-5887T>C		intron	N/A	NP_001139189.2	Q8N8W4-1
	PNPLA1	NM_001145716.2		c.-80-5887T>C		intron	N/A	NP_001139188.1	Q8N8W4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA1	ENST00000636260.2	TSL:5 MANE Select	c.206-5887T>C		intron	N/A	ENSP00000490785.2	A0A1B0GW56
	PNPLA1	ENST00000457797.5	TSL:1	c.206-5887T>C		intron	N/A	ENSP00000391868.1	A0A0C4DG24
	PNPLA1	ENST00000394571.3	TSL:1	c.206-5887T>C		intron	N/A	ENSP00000378072.2	Q8N8W4-1

Frequencies

GnomAD3 genomes AF: 0.645 AC: 98046 AN: 151960 Hom.: 31650 Cov.: 32

Gnomad AFR AF: 0.659

Gnomad AMI AF: 0.497

Gnomad AMR AF: 0.680

Gnomad ASJ AF: 0.674

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.697

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

GnomAD4 genome AF: 0.645 AC: 98118 AN: 152080 Hom.: 31677 Cov.: 32 AF XY: 0.641 AC XY: 47670 AN XY: 74382

African (AFR) AF: 0.659 AC: 27317 AN: 41472

American (AMR) AF: 0.680 AC: 10409 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 2338 AN: 3468

East Asian (EAS) AF: 0.629 AC: 3251 AN: 5168

South Asian (SAS) AF: 0.541 AC: 2610 AN: 4820

European-Finnish (FIN) AF: 0.589 AC: 6227 AN: 10578

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.645 AC: 43830 AN: 67964

Other (OTH) AF: 0.701 AC: 1480 AN: 2110

Alfa AF: 0.642 Hom.: 4452

Bravo AF: 0.657

Asia WGS AF: 0.656 AC: 2282 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		0.57
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: rs1467912; hg19: chr6-36253210; COSMIC: COSV57234356;