7-108472458-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001256007.3(PNPLA8):c.2292T>C(p.Asp764=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,597,154 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (20 hom.)
• Consequence: PNPLA8 NM_001256007.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.259

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 7-108472458-A-G is Benign according to our data. Variant chr7-108472458-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 782747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.259 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00244 (372/152248) while in subpopulation NFE AF= 0.00447 (304/67994). AF 95% confidence interval is 0.00406. There are 2 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA8	NM_001256007.3	c.2292T>C	p.Asp764=	synonymous_variant	11/11	ENST00000257694.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA8	ENST00000257694.13	c.2292T>C	p.Asp764=	synonymous_variant	11/11	1	NM_001256007.3	P1

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 372 AN: 152130 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00206 AC: 496 AN: 240480 Hom.: 1 AF XY: 0.00215 AC XY: 280 AN XY: 129978

Gnomad AFR exome AF: 0.000696

Gnomad AMR exome AF: 0.000798

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00209

Gnomad FIN exome AF: 0.000514

Gnomad NFE exome AF: 0.00347

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.00414 AC: 5984 AN: 1444906 Hom.: 20 Cov.: 27 AF XY: 0.00403 AC XY: 2896 AN XY: 719064

Gnomad4 AFR exome AF: 0.000835

Gnomad4 AMR exome AF: 0.000991

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00215

Gnomad4 FIN exome AF: 0.000902

Gnomad4 NFE exome AF: 0.00494

Gnomad4 OTH exome AF: 0.00397

GnomAD4 genome AF: 0.00244 AC: 372 AN: 152248 Hom.: 2 Cov.: 32 AF XY: 0.00218 AC XY: 162 AN XY: 74454

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00271 Hom.: 0

Bravo AF: 0.00234

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PNPLA8: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	5.6
Dann	Benign	0.53

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: rs141467024; hg19: chr7-108112902; COSMIC: COSV99993955; COSMIC: COSV99993955;