rs12199580

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 15/20 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

Publications

25 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: Benign. The variant received -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 VariationId is 257569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
PNPLA1	NM_001374623.1 link	c.1268C>A	p.Pro423His	missense_variant	Exon 6 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.1268C>A	p.Pro423His	missense_variant	Exon 6 of 9	5	NM_001374623.1	ENSP00000490785.2		A0A1B0GW56
PNPLA1	ENST00000457797.5 link	c.1271C>A	p.Pro424His	missense_variant	Exon 6 of 8	1		ENSP00000391868.1		A0A0C4DG24

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

GnomAD2 exomes

AF:

0.396

AC:

98668

AN:

249434

AF XY:

0.390

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 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

African (AFR)

AF:

0.183

AC:

6121

AN:

33456

American (AMR)

AF:

0.547

AC:

24432

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

9830

AN:

25968

East Asian (EAS)

AF:

0.207

AC:

8196

AN:

39656

South Asian (SAS)

AF:

0.308

AC:

26498

AN:

86120

European-Finnish (FIN)

AF:

0.443

AC:

23614

AN:

53272

Middle Eastern (MID)

AF:

0.263

AC:

1516

AN:

5756

European-Non Finnish (NFE)

AF:

0.428

AC:

474727

AN:

1110446

Other (OTH)

AF:

0.375

AC:

22607

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

22952

45903

68855

91806

114758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14348

28696

43044

57392

71740

<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:

0.354

AC:

53893

AN:

152048

Hom.:

10605

Cov.:

AF XY:

0.356

AC XY:

26489

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.200

AC:

8292

AN:

41474

American (AMR)

AF:

0.439

AC:

6710

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.367

AC:

1273

AN:

3466

East Asian (EAS)

AF:

0.194

AC:

998

AN:

5156

South Asian (SAS)

AF:

0.289

AC:

1393

AN:

4818

European-Finnish (FIN)

AF:

0.454

AC:

4796

AN:

10564

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.430

AC:

29236

AN:

67956

Other (OTH)

AF:

0.303

AC:

641

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1740

3480

5220

6960

8700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

526

1052

1578

2104

2630

<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:

0.397

Hom.:

42359

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

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive congenital ichthyosis 10

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

0.18

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

Mutation Taster

=100/0

polymorphism (auto)

(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