6-36270616-T-C

Position:

• chr6-36270616-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001374623.1(PNPLA1):​c.157T>C​(p.Ser53Pro) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S53W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNPLA1 NM_001374623.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.48

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001374623.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-36270617-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 684647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 6-36270616-T-C is Pathogenic according to our data. Variant chr6-36270616-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 684646.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA1	NM_001374623.1	c.157T>C	p.Ser53Pro	missense_variant	1/9	ENST00000636260.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA1	ENST00000636260.2	c.157T>C	p.Ser53Pro	missense_variant	1/9	5	NM_001374623.1	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital ichthyosiform erythroderma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Jun 07, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	.;D
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;M
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.89
MutPred		0.86		Loss of catalytic residue at S53 (P = 0.0281);Loss of catalytic residue at S53 (P = 0.0281);
MVP		0.94
MPC		0.88
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1582046125; hg19: chr6-36238393;