rs774184465

Variant names:

• chr7-108472473-CAG-C
• rs774184465
• NM_001256007.3:c.2275_2276delCT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 7.08

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 0 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 ClinVar 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 Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.0000165 AC: 4 AN: 242202 Hom.: 0 AF XY: 0.0000153 AC XY: 2 AN XY: 130890

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 SAS 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: 11 AN: 1447946 Hom.: 0 AF XY: 0.00000972 AC XY: 7 AN XY: 720412

Gnomad4 AFR exome AF: 0.0000920

Gnomad4 AMR exome AF: 0.0000232

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74336

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

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

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

LitVar

Other links and lift over

dbSNP: rs774184465; hg19: chr7-108112917;