chrX-7922028-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_004650.3(PNPLA4):c.251G>A(p.Gly84Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000119 in 1,206,143 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 46 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G84S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.00012 ( 0 hom. 45 hem. )

Consequence

PNPLA4
NM_004650.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.13

Publications

1 publications found

Variant links:

Genes affected

PNPLA4 (HGNC:24887): (patatin like phospholipase domain containing 4) This gene encodes a member of the patatin-like family of phospholipases. The encoded enzyme has both triacylglycerol lipase and transacylase activities and may be involved in adipocyte triglyceride homeostasis. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome Y. [provided by RefSeq, Feb 2010]

PNPLA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.76

BS2

High Hemizygotes in GnomAdExome4 at 45 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA4	NM_004650.3 link	c.251G>A	p.Gly84Asp	missense_variant	Exon 3 of 7	ENST00000381042.9	NP_004641.1	P41247-1A0A024RBU8
PNPLA4	NM_001142389.2 link	c.251G>A	p.Gly84Asp	missense_variant	Exon 3 of 7		NP_001135861.1	P41247-1A0A024RBU8
PNPLA4	NM_001172672.2 link	c.-11G>A		5_prime_UTR_variant	Exon 2 of 6		NP_001166143.1	P41247-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PNPLA4	ENST00000381042.9 link	c.251G>A	p.Gly84Asp	missense_variant	Exon 3 of 7	1	NM_004650.3	ENSP00000370430.4	P41247-1
PNPLA4	ENST00000444736.5 link	c.251G>A	p.Gly84Asp	missense_variant	Exon 3 of 7	4		ENSP00000415245.1	P41247-1
PNPLA4	ENST00000442940.1 link	c.251G>A	p.Gly84Asp	missense_variant	Exon 3 of 6	2		ENSP00000406698.1	C9IZF6
PNPLA4	ENST00000537427.5 link	c.-11G>A		5_prime_UTR_variant	Exon 2 of 6	2		ENSP00000443157.1	P41247-2

Frequencies

GnomAD3 genomes

AF:

0.0000716

AC:

AN:

111801

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000441

AC:

AN:

181285

AF XY:

0.0000760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000990

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

136

AN:

1094342

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

359856

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26330

American (AMR)

AF:

0.00

AC:

AN:

35167

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19350

East Asian (EAS)

AF:

0.00

AC:

AN:

30186

South Asian (SAS)

AF:

0.00

AC:

AN:

53844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40479

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.000155

AC:

130

AN:

838896

Other (OTH)

AF:

0.000109

AC:

AN:

45968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000716

AC:

AN:

111801

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

33987

show subpopulations

African (AFR)

AF:

0.0000652

AC:

AN:

30674

American (AMR)

AF:

0.00

AC:

AN:

10572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3555

South Asian (SAS)

AF:

0.00

AC:

AN:

2643

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53231

Other (OTH)

AF:

0.00

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000174

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 04, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.251G>A (p.G84D) alteration is located in exon 3 (coding exon 2) of the PNPLA4 gene. This alteration results from a G to A substitution at nucleotide position 251, causing the glycine (G) at amino acid position 84 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.048

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;D;D

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

.;D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Uncertain

0.052

MutationAssessor

Uncertain

2.4

M;M;.

PhyloP100

4.1

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.1

D;D;D

REVEL

Pathogenic

0.67

Sift

Benign

0.075

T;T;D

Sift4G

Benign

0.18

T;T;T

Polyphen

0.99

D;D;.

Vest4

0.91

MVP

0.44

MPC

0.29

ClinPred

0.72

GERP RS

4.6

Varity_R

0.78

gMVP

0.58

Mutation Taster

=292/8

polymorphism

(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