rs12199580

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001374623.1(PNPLA1):c.1268C>A(p.Pro423His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 1,611,662 control chromosomes in the GnomAD database, including 137,027 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10605 hom., cov: 32)

Exomes 𝑓: 0.41 ( 126422 hom. )

Consequence

PNPLA1
NM_001374623.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.183

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.4265744E-5).

BP6

Variant 6-36302353-C-A is Benign according to our data. Variant chr6-36302353-C-A is described in ClinVar as [Benign]. Clinvar id is 257569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-36302353-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA1	NM_001374623.1 linkuse as main transcript	c.1268C>A	p.Pro423His	missense_variant	6/9	ENST00000636260.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA1	ENST00000636260.2 linkuse as main transcript	c.1268C>A	p.Pro423His	missense_variant	6/9	5	NM_001374623.1	A2

Frequencies

GnomAD3 genomes

AF:

0.354

AC:

53841

AN:

151930

Hom.:

10592

Cov.:

show subpopulations

Gnomad AFR

AF:

0.200

Gnomad AMI

AF:

0.539

Gnomad AMR

AF:

0.438

Gnomad ASJ

AF:

0.367

Gnomad EAS

AF:

0.193

Gnomad SAS

AF:

0.288

Gnomad FIN

AF:

0.454

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.430

Gnomad OTH

AF:

0.308

GnomAD3 exomes

AF:

0.396

AC:

98668

AN:

249434

Hom.:

21236

AF XY:

0.390

AC XY:

52608

AN XY:

134762

show subpopulations

Gnomad AFR exome

AF:

0.194

Gnomad AMR exome

AF:

0.563

Gnomad ASJ exome

AF:

0.380

Gnomad EAS exome

AF:

0.187

Gnomad SAS exome

AF:

0.308

Gnomad FIN exome

AF:

0.447

Gnomad NFE exome

AF:

0.422

Gnomad OTH exome

AF:

0.400

GnomAD4 exome

AF:

0.409

AC:

597541

AN:

1459614

Hom.:

126422

Cov.:

AF XY:

0.405

AC XY:

294166

AN XY:

725760

show subpopulations

Gnomad4 AFR exome

AF:

0.183

Gnomad4 AMR exome

AF:

0.547

Gnomad4 ASJ exome

AF:

0.379

Gnomad4 EAS exome

AF:

0.207

Gnomad4 SAS exome

AF:

0.308

Gnomad4 FIN exome

AF:

0.443

Gnomad4 NFE exome

AF:

0.428

Gnomad4 OTH exome

AF:

0.375

GnomAD4 genome

AF:

0.354

AC:

53893

AN:

152048

Hom.:

10605

Cov.:

AF XY:

0.356

AC XY:

26489

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.200

Gnomad4 AMR

AF:

0.439

Gnomad4 ASJ

AF:

0.367

Gnomad4 EAS

AF:

0.194

Gnomad4 SAS

AF:

0.289

Gnomad4 FIN

AF:

0.454

Gnomad4 NFE

AF:

0.430

Gnomad4 OTH

AF:

0.303

Alfa

AF:

0.396

Hom.:

18552

Bravo

AF:

0.347

TwinsUK

AF:

0.424

AC:

1573

ALSPAC

AF:

0.427

AC:

1644

ESP6500AA

AF:

0.207

AC:

913

ESP6500EA

AF:

0.433

AC:

3723

ExAC

AF:

0.385

AC:

46774

Asia WGS

AF:

0.218

AC:

760

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Autosomal recessive congenital ichthyosis 10

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0059

.;.;.;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.55

T;T;T;T

MetaRNN

Benign

0.000034

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

.;.;.;L

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Benign

0.033

Sift

Benign

0.14

T;T;T;T

Sift4G

Benign

0.34

T;T;T;T

Polyphen

0.043

B;.;.;B

Vest4

0.083

MPC

0.24

ClinPred

0.0029

GERP RS

1.7

Varity_R

0.054

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over