7-108472473-CAG-C

Variant names:

• chr7-108472472-GCA-GC
• NM_001256007.3:c.2276delT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001256007.3(PNPLA8):​c.2276delT​(p.Leu759ArgfsTer8) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNPLA8 NM_001256007.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 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 0.0311 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256007.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA8	NM_001256007.3	MANE Select	c.2276delT	p.Leu759ArgfsTer8	frameshift	Exon 11 of 11	NP_001242936.1	Q9NP80-1
	PNPLA8	NM_001256008.3		c.2276delT	p.Leu759ArgfsTer8	frameshift	Exon 10 of 10	NP_001242937.1	Q9NP80-1
	PNPLA8	NM_015723.5		c.2276delT	p.Leu759ArgfsTer8	frameshift	Exon 12 of 12	NP_056538.1	Q9NP80-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNPLA8	ENST00000257694.13	TSL:1 MANE Select	c.2276delT	p.Leu759ArgfsTer8	frameshift	Exon 11 of 11	ENSP00000257694.8	Q9NP80-1
	PNPLA8	ENST00000422087.5	TSL:1	c.2276delT	p.Leu759ArgfsTer8	frameshift	Exon 12 of 12	ENSP00000410804.1	Q9NP80-1
	PNPLA8	ENST00000436062.5	TSL:1	c.2276delT	p.Leu759ArgfsTer8	frameshift	Exon 10 of 10	ENSP00000406779.1	Q9NP80-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr7-108112916;