Genetic Variant NM_001374623.1:c.1469C>A (chr6-36306376-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001374623.1(PNPLA1):c.1469C>A(p.Thr490Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,678 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T490M) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PNPLA1
NM_001374623.1 missense, splice_region

Scores

Splicing: ADA: 0.00006405

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04282731).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA1	NM_001374623.1 link	c.1469C>A	p.Thr490Lys	missense_variant, splice_region_variant	Exon 7 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.1469C>A	p.Thr490Lys	missense_variant, splice_region_variant	Exon 7 of 9	5	NM_001374623.1	ENSP00000490785.2		A0A1B0GW56
PNPLA1	ENST00000457797.5 link	c.1472C>A	p.Thr491Lys	missense_variant, splice_region_variant	Exon 7 of 8	1		ENSP00000391868.1		A0A0C4DG24

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1454678

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

723750

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0020

DANN

Benign

0.61

DEOGEN2

Benign

0.00067

.;.;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0073

LIST_S2

Benign

0.13

T;T;T;T

M_CAP

Benign

0.0036

MetaRNN

Benign

0.043

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

.;.;.;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.070

N;N;N;N

REVEL

Benign

0.013

Sift

Uncertain

0.024

D;D;D;D

Sift4G

Benign

0.38

T;T;T;T

Polyphen

0.0

B;.;.;B

Vest4

0.043

MutPred

0.29

.;.;.;Gain of solvent accessibility (P = 0.0044);

MVP

0.081

MPC

0.24

ClinPred

0.11

GERP RS

-3.4

Varity_R

0.057

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000064

dbscSNV1_RF

Benign

0.0020

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over