Genetic Variant PNPLA7:p.Pro933Gln (chr9-137478118-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001098537.3(PNPLA7):c.2798C>A(p.Pro933Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000167 in 1,195,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

PNPLA7
NM_001098537.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.26

Publications

10 publications found

Variant links:

Genes affected

PNPLA7 (HGNC:24768): (patatin like phospholipase domain containing 7) Human patatin-like phospholipases, such as PNPLA7, have been implicated in regulation of adipocyte differentiation and have been induced by metabolic stimuli (Wilson et al., 2006 [PubMed 16799181]).[supplied by OMIM, Jun 2008]

PNPLA7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.777

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA7	NM_001098537.3 link	c.2798C>A	p.Pro933Gln	missense_variant	Exon 25 of 35	ENST00000406427.6	NP_001092007.2	Q6ZV29-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PNPLA7	ENST00000406427.6 link	c.2798C>A	p.Pro933Gln	missense_variant	Exon 25 of 35	1	NM_001098537.3	ENSP00000384610.1	Q6ZV29-5
PNPLA7	ENST00000277531.8 link	c.2723C>A	p.Pro908Gln	missense_variant	Exon 24 of 34	2		ENSP00000277531.4	Q6ZV29-1
PNPLA7	ENST00000469998.1 link	n.1537C>A		non_coding_transcript_exon_variant	Exon 2 of 10	2
PNPLA7	ENST00000492278.5 link	n.1314C>A		non_coding_transcript_exon_variant	Exon 1 of 5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000167

AC:

AN:

1195354

Hom.:

Cov.:

AF XY:

0.00000173

AC XY:

AN XY:

576496

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23850

American (AMR)

AF:

0.00

AC:

AN:

10608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16662

East Asian (EAS)

AF:

0.00

AC:

AN:

27310

South Asian (SAS)

AF:

0.00

AC:

AN:

46662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4888

European-Non Finnish (NFE)

AF:

0.00000205

AC:

AN:

974324

Other (OTH)

AF:

0.00

AC:

AN:

48154

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

0.0034

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.063

T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.9

L;.

PhyloP100

9.3

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Benign

0.26

Sift

Benign

0.040

D;D

Sift4G

Benign

0.086

T;T

Polyphen

0.98

D;D

Vest4

0.52

MutPred

0.20

Loss of catalytic residue at P907 (P = 0.0185);.;

MVP

0.27

MPC

0.67

ClinPred

1.0

GERP RS

4.7

Varity_R

0.19

gMVP

0.49

Mutation Taster

=59/41

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over