6-36307681-T-A

Variant names:

• chr6-36307681-T-A
• rs4713956
• NM_001374623.1:c.1564T>A

Variant summary

Our verdict is Likely benign. The variant received -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. 16/21 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
• Publications: 34 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: Likely_benign. The variant received -2 ACMG points.

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

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.1564T>A	p.Ser522Thr	missense	Exon 8 of 9	NP_001361552.1	A0A1B0GW56
	PNPLA1	NM_001145717.1		c.1564T>A	p.Ser522Thr	missense	Exon 8 of 8	NP_001139189.2	Q8N8W4-1
	PNPLA1	NM_001145716.2		c.1306T>A	p.Ser436Thr	missense	Exon 8 of 8	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.1564T>A	p.Ser522Thr	missense	Exon 8 of 9	ENSP00000490785.2	A0A1B0GW56
	PNPLA1	ENST00000457797.5	TSL:1	c.1567T>A	p.Ser523Thr	missense	Exon 8 of 8	ENSP00000391868.1	A0A0C4DG24
	PNPLA1	ENST00000394571.3	TSL:1	c.1564T>A	p.Ser522Thr	missense	Exon 8 of 8	ENSP00000378072.2	Q8N8W4-1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.44
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.014
Sift	Benign	0.048	D
Sift4G	Benign	0.11	T
Polyphen		0.0020	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
Mutation Taster		=100/0	polymorphism

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: rs4713956; hg19: chr6-36275458;