rs1561853847

Variant names:

• chr6-36270635-C-T
• rs1561853847
• NM_001374623.1:c.176C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001374623.1(PNPLA1):​c.176C>T​(p.Ala59Val) 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. A59T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNPLA1 NM_001374623.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.40
• Publications: 0 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, PanelApp Australia
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001374623.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 6-36270635-C-T is Pathogenic according to our data. Variant chr6-36270635-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 39562.Status of the report is no_assertion_criteria_provided, 0 stars.

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.176C>T	p.Ala59Val	missense	Exon 1 of 9	NP_001361552.1	A0A1B0GW56
	PNPLA1	NM_001145717.1		c.176C>T	p.Ala59Val	missense	Exon 1 of 8	NP_001139189.2	Q8N8W4-1
	PNPLA1	NM_001145716.2		c.-80-20685C>T		intron	N/A	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.176C>T	p.Ala59Val	missense	Exon 1 of 9	ENSP00000490785.2	A0A1B0GW56
	PNPLA1	ENST00000457797.5	TSL:1	c.176C>T	p.Ala59Val	missense	Exon 1 of 8	ENSP00000391868.1	A0A0C4DG24
	PNPLA1	ENST00000394571.3	TSL:1	c.176C>T	p.Ala59Val	missense	Exon 1 of 8	ENSP00000378072.2	Q8N8W4-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive congenital ichthyosis 10 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.79		Loss of helix (P = 0.0626)
MPC		0.78
ClinPred		0.98	D
GERP RS		4.5
PromoterAI		0.015	Neutral
Varity_R		0.47
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1561853847; hg19: chr6-36238412;