NM_001256007.3:c.2275_2276delCT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_001256007.3(PNPLA8):c.2275_2276delCT(p.Leu759AlafsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000875 in 1,600,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

PNPLA8
NM_001256007.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: 7.08

Publications

3 publications found

Variant links:

Genes affected

PNPLA8 (HGNC:28900): (patatin like phospholipase domain containing 8) This gene encodes a member of the patatin-like phospholipase domain containing protein family. Members of this family are phospholipases which catalyze the cleavage of fatty acids from membrane phospholipids. The product of this gene is a calcium-independent phospholipase. Mutations in this gene have been associated with mitochondrial myopathy with lactic acidosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2015]

PNPLA8 Gene-Disease associations (from GenCC):

mitochondrial myopathy-lactic acidosis-deafness syndrome
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

PNPLA8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0315 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-108472473-CAG-C is Pathogenic according to our data. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-108472473-CAG-C is described in CliVar as Pathogenic. Clinvar id is 190128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA8	NM_001256007.3 link	c.2275_2276delCT	p.Leu759AlafsTer4	frameshift_variant	Exon 11 of 11	ENST00000257694.13	NP_001242936.1	Q9NP80-1A0A024R746

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNPLA8	ENST00000257694.13 link	c.2275_2276delCT	p.Leu759AlafsTer4	frameshift_variant	Exon 11 of 11	1	NM_001256007.3	ENSP00000257694.8		Q9NP80-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000165

AC:

AN:

242202

AF XY:

0.0000153

show subpopulations

Gnomad AFR exome

AF:

0.000190

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000760

AC:

AN:

1447946

Hom.:

AF XY:

0.00000972

AC XY:

AN XY:

720412

show subpopulations

African (AFR)

AF:

0.0000920

AC:

AN:

32612

American (AMR)

AF:

0.0000232

AC:

AN:

43056

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25874

East Asian (EAS)

AF:

0.00

AC:

AN:

39570

South Asian (SAS)

AF:

0.0000238

AC:

AN:

83954

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1104098

Other (OTH)

AF:

0.0000334

AC:

AN:

59802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial myopathy-lactic acidosis-deafness syndrome

Pathogenic:2

Mar 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 05, 2021

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Jul 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Leu759Alafs*4) in the PNPLA8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the PNPLA8 protein. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 190128). This variant is also known as c.1975_1976delAG. This premature translational stop signal has been observed in individual(s) with mitochondrial myopathy with lactic acidosis (PMID: 25512002, 29681094). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs774184465, gnomAD 0.02%). -

not specified

Uncertain:1

Nov 23, 2016

GeneDx

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

The c.2275_2276delCT variant in the PNPLA8 gene has been reported previously in an individual with a suspected mitochondrial myopathy, with progressive muscle weakness, hypotonia, seizures, poor weight gain, and lactic acidosis, who was compound heterozygous for the c.2275_2276delCT variant and another loss of function variant (Saunders et al., 2015). The c.2275_2276delCT variant causes a frameshift starting with codon Leucine 759, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Leu759AlafsX4. This variant is predicted to cause loss of normal protein function through protein truncation. The c.2275_2276delCT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2275_2276delCT as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.1

Mutation Taster

=0/200

disease causing

(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