rs781053760

Variant names:

• chr6-36291532-T-C
• rs781053760
• NM_001374623.1:c.418T>C
• PNPLA1 p.Ser140Pro

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS1_Very_Strong PM2 PP3 PP5_Very_Strong

The NM_001374623.1(PNPLA1):​c.418T>C​(p.Ser140Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,325,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000025 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PNPLA1 NM_001374623.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.18
• 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), G2P, Genomics England PanelApp, Ambry Genetics
• congenital non-bullous ichthyosiform erythroderma

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS1: Transcript NM_001374623.1 (PNPLA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788
• PP5: Variant 6-36291532-T-C is Pathogenic according to our data. Variant chr6-36291532-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.418T>C	p.Ser140Pro	missense	Exon 2 of 9	NP_001361552.1	A0A1B0GW56
	PNPLA1	NM_001145717.1		c.418T>C	p.Ser140Pro	missense	Exon 2 of 8	NP_001139189.2	Q8N8W4-1
	PNPLA1	NM_001145716.2		c.133T>C	p.Ser45Pro	missense	Exon 2 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.418T>C	p.Ser140Pro	missense	Exon 2 of 9	ENSP00000490785.2	A0A1B0GW56
	PNPLA1	ENST00000457797.5	TSL:1	c.418T>C	p.Ser140Pro	missense	Exon 2 of 8	ENSP00000391868.1	A0A0C4DG24
	PNPLA1	ENST00000394571.3	TSL:1	c.418T>C	p.Ser140Pro	missense	Exon 2 of 8	ENSP00000378072.2	Q8N8W4-1

Frequencies

GnomAD3 genomes AF: 0.0000254 AC: 3 AN: 117946 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000121

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000824 AC: 2 AN: 242832 AF XY: 0.00000763

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000166 AC: 20 AN: 1207852 Hom.: 0 Cov.: 33 AF XY: 0.0000117 AC XY: 7 AN XY: 597248

African (AFR) AF: 0.00 AC: 0 AN: 26174

American (AMR) AF: 0.00 AC: 0 AN: 36848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16784

East Asian (EAS) AF: 0.00 AC: 0 AN: 16518

South Asian (SAS) AF: 0.00 AC: 0 AN: 83110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32092

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4456

European-Non Finnish (NFE) AF: 0.0000211 AC: 20 AN: 948150

Other (OTH) AF: 0.00 AC: 0 AN: 43720

GnomAD4 genome AF: 0.0000254 AC: 3 AN: 117946 Hom.: 0 Cov.: 29 AF XY: 0.0000185 AC XY: 1 AN XY: 54026

African (AFR) AF: 0.00 AC: 0 AN: 30896

American (AMR) AF: 0.000121 AC: 1 AN: 8268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3258

East Asian (EAS) AF: 0.00 AC: 0 AN: 3350

South Asian (SAS) AF: 0.00 AC: 0 AN: 3410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 148

European-Non Finnish (NFE) AF: 0.0000323 AC: 2 AN: 61838

Other (OTH) AF: 0.00 AC: 0 AN: 1618

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Autosomal recessive congenital ichthyosis 10 (3)
1	-	-	Congenital ichthyosiform erythroderma (1)
1	-	-	Lamellar ichthyosis (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.023	D
Varity_R		0.56
Mutation Taster		=5/95	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs781053760;

hg19: chr6-36259309;