rs922934422

Variant names:

• chr6-36291380-C-T
• rs922934422
• NM_001374623.1:c.266C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001374623.1(PNPLA1):​c.266C>T​(p.Pro89Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P89T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PNPLA1 NM_001374623.1 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.01
• Publications: 2 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919
• PP5: Variant 6-36291380-C-T is Pathogenic according to our data. Variant chr6-36291380-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 375259.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA1	NM_001374623.1	c.266C>T	p.Pro89Leu	missense_variant	Exon 2 of 9	ENST00000636260.2	NP_001361552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA1	ENST00000636260.2	c.266C>T	p.Pro89Leu	missense_variant	Exon 2 of 9	5	NM_001374623.1	ENSP00000490785.2
PNPLA1	ENST00000457797.5	c.266C>T	p.Pro89Leu	missense_variant	Exon 2 of 8	1		ENSP00000391868.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive congenital ichthyosis 10 Pathogenic:1

-

Unité de Différenciation Epithéliale et Auto-Immunité Rhumatoïde, INSERM - Université Paul Sabatier

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation;research

This variant has been seen as a compound heterozygote with this variant : c.[418T>C], [p.Ser140Pro] -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.8	.;L
PhyloP100		7.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Uncertain	0.61
Sift	Benign	0.040	D;D
Sift4G	Uncertain	0.046	D;D
Polyphen		0.99	.;D
Vest4		0.94
MutPred		0.68		Gain of catalytic residue at P89 (P = 0.0232);Gain of catalytic residue at P89 (P = 0.0232);
MVP		0.90
MPC		0.69
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.25
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs922934422; hg19: chr6-36259157;