NM_001374623.1:c.1564T>C

Variant names:

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.1564T>C(p.Ser522Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 1,613,324 control chromosomes in the GnomAD database, including 333,542 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S522L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.66 ( 33275 hom., cov: 30)

Exomes 𝑓: 0.64 ( 300267 hom. )

Consequence

PNPLA1
NM_001374623.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.443

Publications

34 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=1.863658E-6).

BP6

Variant 6-36307681-T-C is Benign according to our data. Variant chr6-36307681-T-C is described in ClinVar as Benign. ClinVar VariationId is 257571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA1	NM_001374623.1 link	c.1564T>C	p.Ser522Pro	missense_variant	Exon 8 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.1564T>C	p.Ser522Pro	missense_variant	Exon 8 of 9	5	NM_001374623.1	ENSP00000490785.2		A0A1B0GW56
PNPLA1	ENST00000457797.5 link	c.1567T>C	p.Ser523Pro	missense_variant	Exon 8 of 8	1		ENSP00000391868.1		A0A0C4DG24

Frequencies

GnomAD3 genomes

AF:

0.660

AC:

100151

AN:

151726

Hom.:

33240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.725

Gnomad AMI

AF:

0.592

Gnomad AMR

AF:

0.666

Gnomad ASJ

AF:

0.430

Gnomad EAS

AF:

0.576

Gnomad SAS

AF:

0.577

Gnomad FIN

AF:

0.675

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.642

Gnomad OTH

AF:

0.649

GnomAD2 exomes

AF:

0.639

AC:

160448

AN:

251240

AF XY:

0.629

show subpopulations

Gnomad AFR exome

AF:

0.728

Gnomad AMR exome

AF:

0.724

Gnomad ASJ exome

AF:

0.433

Gnomad EAS exome

AF:

0.574

Gnomad FIN exome

AF:

0.674

Gnomad NFE exome

AF:

0.641

Gnomad OTH exome

AF:

0.623

GnomAD4 exome

AF:

0.639

AC:

934187

AN:

1461480

Hom.:

300267

Cov.:

AF XY:

0.635

AC XY:

461746

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.729

AC:

24390

AN:

33474

American (AMR)

AF:

0.718

AC:

32108

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.438

AC:

11435

AN:

26122

East Asian (EAS)

AF:

0.580

AC:

23002

AN:

39676

South Asian (SAS)

AF:

0.571

AC:

49236

AN:

86230

European-Finnish (FIN)

AF:

0.679

AC:

36228

AN:

53390

Middle Eastern (MID)

AF:

0.557

AC:

3212

AN:

5768

European-Non Finnish (NFE)

AF:

0.645

AC:

716899

AN:

1111748

Other (OTH)

AF:

0.624

AC:

37677

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

18028

36055

54083

72110

90138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18902

37804

56706

75608

94510

<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:

0.660

AC:

100243

AN:

151844

Hom.:

33275

Cov.:

AF XY:

0.657

AC XY:

48737

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.725

AC:

30017

AN:

41398

American (AMR)

AF:

0.667

AC:

10168

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.430

AC:

1494

AN:

3472

East Asian (EAS)

AF:

0.576

AC:

2957

AN:

5132

South Asian (SAS)

AF:

0.576

AC:

2774

AN:

4818

European-Finnish (FIN)

AF:

0.675

AC:

7086

AN:

10498

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.642

AC:

43655

AN:

67964

Other (OTH)

AF:

0.655

AC:

1380

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1718

3436

5155

6873

8591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

794

1588

2382

3176

3970

<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:

0.640

Hom.:

155876

Bravo

AF:

0.666

TwinsUK

AF:

0.643

AC:

2385

ALSPAC

AF:

0.640

AC:

2467

ESP6500AA

AF:

0.722

AC:

3180

ESP6500EA

AF:

0.630

AC:

5415

ExAC

AF:

0.640

AC:

77669

Asia WGS

AF:

0.642

AC:

2232

AN:

3478

EpiCase

AF:

0.622

EpiControl

AF:

0.620

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 03, 2021

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

Significance:Benign

Review Status:criteria provided, single submitter

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 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31864761) -

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

0.048

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.0

(source)

DANN

Benign

0.081

DEOGEN2

Benign

0.0013

.;.;.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.00030

LIST_S2

Benign

0.12

T;T;T;T

MetaRNN

Benign

0.0000019

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-1.8

.;.;.;N

PhyloP100

0.44

PrimateAI

Benign

0.26

PROVEAN

Benign

0.57

N;N;N;N

REVEL

Benign

0.037

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;.;.;B

Vest4

0.050

MPC

0.25

ClinPred

0.0074

GERP RS

2.5

Varity_R

0.035

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