rs112133109

chr19-7559055-G-Achr19-7559055-G-C

Variant summary

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

The NM_001166114.2(PNPLA6):c.3603G>A(p.Gln1201=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,218 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (13 hom., cov: 33)
  • Exomes 𝑓: 0.013 (140 hom.)
• Consequence: PNPLA6 NM_001166114.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.68

Genes affected

PNPLA6 (HGNC:16268): (patatin like phospholipase domain containing 6) This gene encodes a phospholipase that deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine. It is thought to function in neurite outgrowth and process elongation during neuronal differentiation. The protein is anchored to the cytoplasmic face of the endoplasmic reticulum in both neurons and non-neuronal cells. Mutations in this gene result in autosomal recessive spastic paraplegia, and the protein is the target for neurodegeneration induced by organophosphorus compounds and chemical warfare agents. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 19-7559055-G-A is Benign according to our data. Variant chr19-7559055-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 240699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7559055-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00918 (1399/152356) while in subpopulation NFE AF= 0.0137 (933/68028). AF 95% confidence interval is 0.013. There are 13 homozygotes in gnomad4. There are 677 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA6	NM_001166114.2	c.3603G>A	p.Gln1201=	synonymous_variant	28/32	ENST00000600737.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA6	ENST00000600737.6	c.3603G>A	p.Gln1201=	synonymous_variant	28/32	1	NM_001166114.2	P3

Frequencies

GnomAD3 genomes AF: 0.00921 AC: 1402 AN: 152238 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00248

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0106 AC: 2661 AN: 251440 Hom.: 21 AF XY: 0.0115 AC XY: 1558 AN XY: 135918

Gnomad AFR exome AF: 0.00339

Gnomad AMR exome AF: 0.00627

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00728

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.0128 AC: 18717 AN: 1461862 Hom.: 140 Cov.: 36 AF XY: 0.0129 AC XY: 9350 AN XY: 727232

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00642

Gnomad4 ASJ exome AF: 0.00429

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00780

Gnomad4 FIN exome AF: 0.0138

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.00918 AC: 1399 AN: 152356 Hom.: 13 Cov.: 33 AF XY: 0.00909 AC XY: 677 AN XY: 74508

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00517

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0115 Hom.: 10

Bravo AF: 0.00874

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary spastic paraplegia 39 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 06, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

PNPLA6: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	5.7
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112133109; hg19: chr19-7623941; COSMIC: COSV55386447; COSMIC: COSV55386447;