6-36306376-C-T

Position:

chr6-36306376-C-T

Variant summary

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

The NM_001374623.1(PNPLA1):c.1469C>T(p.Thr490Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,605,392 control chromosomes in the GnomAD database, including 65,828 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6405 hom., cov: 32)

Exomes 𝑓: 0.28 ( 59423 hom. )

Consequence

PNPLA1
NM_001374623.1 missense, splice_region

Scores

Splicing: ADA: 0.0009790

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.41

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=0.003913671).

BP6

Variant 6-36306376-C-T is Benign according to our data. Variant chr6-36306376-C-T is described in ClinVar as [Benign]. Clinvar id is 257570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-36306376-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.316 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.1469C>T	p.Thr490Met	missense_variant, splice_region_variant	7/9	ENST00000636260.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA1	ENST00000636260.2 linkuse as main transcript	c.1469C>T	p.Thr490Met	missense_variant, splice_region_variant	7/9	5	NM_001374623.1	A2

Frequencies

GnomAD3 genomes

AF:

0.284

AC:

43089

AN:

151974

Hom.:

6397

Cov.:

show subpopulations

Gnomad AFR

AF:

0.320

Gnomad AMI

AF:

0.276

Gnomad AMR

AF:

0.203

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.0850

Gnomad SAS

AF:

0.270

Gnomad FIN

AF:

0.302

Gnomad MID

AF:

0.309

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.280

GnomAD3 exomes

AF:

0.258

AC:

62996

AN:

244034

Hom.:

8863

AF XY:

0.263

AC XY:

34679

AN XY:

132074

show subpopulations

Gnomad AFR exome

AF:

0.318

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.246

Gnomad EAS exome

AF:

0.0827

Gnomad SAS exome

AF:

0.279

Gnomad FIN exome

AF:

0.309

Gnomad NFE exome

AF:

0.291

Gnomad OTH exome

AF:

0.264

GnomAD4 exome

AF:

0.282

AC:

409646

AN:

1453298

Hom.:

59423

Cov.:

AF XY:

0.282

AC XY:

204099

AN XY:

723150

show subpopulations

Gnomad4 AFR exome

AF:

0.322

Gnomad4 AMR exome

AF:

0.168

Gnomad4 ASJ exome

AF:

0.249

Gnomad4 EAS exome

AF:

0.0802

Gnomad4 SAS exome

AF:

0.277

Gnomad4 FIN exome

AF:

0.309

Gnomad4 NFE exome

AF:

0.292

Gnomad4 OTH exome

AF:

0.274

GnomAD4 genome

AF:

0.284

AC:

43129

AN:

152094

Hom.:

6405

Cov.:

AF XY:

0.281

AC XY:

20870

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.321

Gnomad4 AMR

AF:

0.203

Gnomad4 ASJ

AF:

0.240

Gnomad4 EAS

AF:

0.0856

Gnomad4 SAS

AF:

0.269

Gnomad4 FIN

AF:

0.302

Gnomad4 NFE

AF:

0.295

Gnomad4 OTH

AF:

0.280

Alfa

AF:

0.286

Hom.:

14096

Bravo

AF:

0.279

TwinsUK

AF:

0.299

AC:

1107

ALSPAC

AF:

0.285

AC:

1100

ESP6500AA

AF:

0.318

AC:

1401

ESP6500EA

AF:

0.287

AC:

2464

ExAC

AF:

0.263

AC:

31867

EpiCase

AF:

0.294

EpiControl

AF:

0.285

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Autosomal recessive congenital ichthyosis 10

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.010

DANN

Benign

0.86

DEOGEN2

Benign

0.00080

.;.;.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.17

T;T;T;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.0039

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.81

.;.;.;N

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.26

PROVEAN

Benign

0.63

N;N;N;N

REVEL

Benign

0.011

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.0

B;.;.;B

Vest4

0.043

MPC

0.21

ClinPred

0.0027

GERP RS

-3.4

Varity_R

0.019

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00098

dbscSNV1_RF

Benign

0.16

SpliceAI score (max)

0.040

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