6-36270559-G-C

Position:

• chr6-36270559-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001374623.1(PNPLA1):​c.100G>C​(p.Ala34Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PNPLA1 NM_001374623.1 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.48

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 6-36270559-G-C is Pathogenic according to our data. Variant chr6-36270559-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1691290.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA1	NM_001374623.1	c.100G>C	p.Ala34Pro	missense_variant	1/9	ENST00000636260.2	NP_001361552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA1	ENST00000636260.2	c.100G>C	p.Ala34Pro	missense_variant	1/9	5	NM_001374623.1	ENSP00000490785	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000648 AC: 1 AN: 154404 Hom.: 0 AF XY: 0.0000122 AC XY: 1 AN XY: 82072

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399248 Hom.: 0 Cov.: 32 AF XY: 0.00000290 AC XY: 2 AN XY: 690144

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive congenital ichthyosis 10 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Mar 28, 2022

The c.100G>C variant is not present in publicly available population databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC) and Indian Exome Database. The heterozygous state of the variant is present in Genome Aggregation Database (gnomAD), at a very low frequency. The variant is not present in our in-house exome database. The variant was previously identified in patients affected with autosomal recessive congenital ichthyosis (PMID:27884779) and reported to Human Genome Mutation Database (HGMD ID: CM172412). In-silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2, CADD, Varsome etc. predicted this variant to be likely deleterious. The variant is located in the mutational hotspot region and an alternate variant in this position (c.100G>A) was also reported in HGMD (ID: CM144452) (PMID:24344921). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	.;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.9	.;M
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		1.0	.;D
Vest4		0.86
MutPred		0.87		Loss of stability (P = 0.1487);Loss of stability (P = 0.1487);
MVP		0.82
MPC		0.89
ClinPred		0.87	D
GERP RS		4.4
Varity_R		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs1182312612; hg19: chr6-36238336;