rs4713956

Positions:

• chr6-36307681-T-A
• chr6-36307681-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001374623.1(PNPLA1):​c.1564T>A​(p.Ser522Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S522P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: PNPLA1 NM_001374623.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.443

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05445227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA1	NM_001374623.1	c.1564T>A	p.Ser522Thr	missense_variant	8/9	ENST00000636260.2	NP_001361552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA1	ENST00000636260.2	c.1564T>A	p.Ser522Thr	missense_variant	8/9	5	NM_001374623.1	ENSP00000490785.2
PNPLA1	ENST00000457797.5	c.1567T>A	p.Ser523Thr	missense_variant	8/8	1		ENSP00000391868.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.3
DANN	Benign	0.78
DEOGEN2	Benign	0.0013	.;.;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.14	T;T;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.054	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	.;.;.;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.23	N;N;N;N
REVEL	Benign	0.014
Sift	Benign	0.048	D;T;D;D
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.0020	B;.;.;B
Vest4		0.097
MutPred		0.18		.;.;.;Gain of relative solvent accessibility (P = 0.1571);
MVP		0.24
MPC		0.18
ClinPred		0.060	T
GERP RS		2.5
Varity_R		0.056

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: rs4713956; hg19: chr6-36275458;