chr6-36307681-T-C

Position:

chr6-36307681-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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=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 id is 257571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-36307681-T-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
PNPLA1	NM_001374623.1 linkuse as main transcript	c.1564T>C	p.Ser522Pro	missense_variant	8/9	ENST00000636260.2	NP_001361552.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA1	ENST00000636260.2 linkuse as main transcript	c.1564T>C	p.Ser522Pro	missense_variant	8/9	5	NM_001374623.1	ENSP00000490785.2		A0A1B0GW56
PNPLA1	ENST00000457797.5 linkuse as main transcript	c.1567T>C	p.Ser523Pro	missense_variant	8/8	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

GnomAD3 exomes

AF:

0.639

AC:

160448

AN:

251240

Hom.:

51931

AF XY:

0.629

AC XY:

85414

AN XY:

135814

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 SAS exome

AF:

0.571

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

Gnomad4 AFR exome

AF:

0.729

Gnomad4 AMR exome

AF:

0.718

Gnomad4 ASJ exome

AF:

0.438

Gnomad4 EAS exome

AF:

0.580

Gnomad4 SAS exome

AF:

0.571

Gnomad4 FIN exome

AF:

0.679

Gnomad4 NFE exome

AF:

0.645

Gnomad4 OTH exome

AF:

0.624

GnomAD4 genome

AF:

0.660

AC:

100243

AN:

151844

Hom.:

33275

Cov.:

AF XY:

0.657

AC XY:

48737

AN XY:

74190

show subpopulations

Gnomad4 AFR

AF:

0.725

Gnomad4 AMR

AF:

0.667

Gnomad4 ASJ

AF:

0.430

Gnomad4 EAS

AF:

0.576

Gnomad4 SAS

AF:

0.576

Gnomad4 FIN

AF:

0.675

Gnomad4 NFE

AF:

0.642

Gnomad4 OTH

AF:

0.655

Alfa

AF:

0.633

Hom.:

79874

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 31864761) -

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

0.048

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.0

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

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

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