6-36270574-GC-GCC

Variant names:

• chr6-36270574-G-GC
• rs1414059926
• NM_001374623.1:c.121dupC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001374623.1(PNPLA1):​c.121dupC​(p.Arg41ProfsTer27) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000429 in 1,399,250 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: PNPLA1 NM_001374623.1 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.41
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.121dupC	p.Arg41ProfsTer27	frameshift	Exon 1 of 9	NP_001361552.1	A0A1B0GW56
	PNPLA1	NM_001145717.1		c.121dupC	p.Arg41ProfsTer27	frameshift	Exon 1 of 8	NP_001139189.2	Q8N8W4-1
	PNPLA1	NM_001145716.2		c.-80-20740dupC		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.121dupC	p.Arg41ProfsTer27	frameshift	Exon 1 of 9	ENSP00000490785.2	A0A1B0GW56
	PNPLA1	ENST00000457797.5	TSL:1	c.121dupC	p.Arg41ProfsTer27	frameshift	Exon 1 of 8	ENSP00000391868.1	A0A0C4DG24
	PNPLA1	ENST00000394571.3	TSL:1	c.121dupC	p.Arg41ProfsTer27	frameshift	Exon 1 of 8	ENSP00000378072.2	Q8N8W4-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000429 AC: 6 AN: 1399250 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690130

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.0000407 AC: 2 AN: 49126

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5692

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078970

Other (OTH) AF: 0.00 AC: 0 AN: 58004

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.4

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: rs1414059926; hg19: chr6-36238351;