rs781053760

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS1_Very_StrongPM2PP3PP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.18

Publications

2 publications found

Variant links:

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), PanelApp Australia, Ambry Genetics, G2P, Genomics England PanelApp
congenital non-bullous ichthyosiform erythroderma
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PNPLA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 as 3335972

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 [Likely_pathogenic]. Clinvar id is 375256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA1	NM_001374623.1 link	c.418T>C	p.Ser140Pro	missense_variant	Exon 2 of 9	ENST00000636260.2	NP_001361552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA1	ENST00000636260.2 link	c.418T>C	p.Ser140Pro	missense_variant	Exon 2 of 9	5	NM_001374623.1	ENSP00000490785.2		A0A1B0GW56
PNPLA1	ENST00000457797.5 link	c.418T>C	p.Ser140Pro	missense_variant	Exon 2 of 8	1		ENSP00000391868.1		A0A0C4DG24

Frequencies

GnomAD3 genomes

AF:

0.0000254

AC:

AN:

117946

Hom.:

Cov.:

show subpopulations

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:

AN:

242832

AF XY:

0.00000763

show subpopulations

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:

AN:

1207852

Hom.:

Cov.:

AF XY:

0.0000117

AC XY:

AN XY:

597248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26174

American (AMR)

AF:

0.00

AC:

AN:

36848

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16784

East Asian (EAS)

AF:

0.00

AC:

AN:

16518

South Asian (SAS)

AF:

0.00

AC:

AN:

83110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4456

European-Non Finnish (NFE)

AF:

0.0000211

AC:

AN:

948150

Other (OTH)

AF:

0.00

AC:

AN:

43720

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000254

AC:

AN:

117946

Hom.:

Cov.:

AF XY:

0.0000185

AC XY:

AN XY:

54026

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30896

American (AMR)

AF:

0.000121

AC:

AN:

8268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3258

East Asian (EAS)

AF:

0.00

AC:

AN:

3350

South Asian (SAS)

AF:

0.00

AC:

AN:

3410

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

148

European-Non Finnish (NFE)

AF:

0.0000323

AC:

AN:

61838

Other (OTH)

AF:

0.00

AC:

AN:

1618

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 10

Pathogenic:3

May 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Unité de Différenciation Epithéliale et Auto-Immunité Rhumatoïde, INSERM - Université Paul Sabatier

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation;research

This variant has been seen as a compound heterozygote in 2 differents families in association with the variant c.[820_820delC],[p.Arg274Glyfs*7]; or with the variant c.[266C>T], [p.Pro89Leu]. -

Jun 10, 2019

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Lamellar ichthyosis

Pathogenic:1

May 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PNPLA1 c.418T>C (p.Ser140Pro) results in a non-conservative amino acid change located in the patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 242832 control chromosomes. c.418T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Lamellar Ichthyosis and has been found to segregate with disease in at least one family (e.g. Pichery_2017, Zimmer_2017, Boyden_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28403545, 28369476, 28093717). ClinVar contains an entry for this variant (Variation ID: 375256). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Aug 23, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31120544, 35893253, 28369476) -

Congenital ichthyosiform erythroderma

Pathogenic:1

Jun 07, 2017

Yale Center for Mendelian Genomics, Yale University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;.;.;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;T;T

M_CAP

Uncertain

0.094

MetaRNN

Pathogenic

0.79

D;D;D;D

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.9

.;.;.;M

PhyloP100

3.2

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-4.7

D;D;D;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.023

D;D;D;D

Polyphen

0.90

P;.;.;D

Vest4

0.57

MutPred

0.73

.;.;Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);

MVP

0.86

MPC

0.35

ClinPred

0.97

GERP RS

4.0

Varity_R

0.56

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over