rs35732838

Positions:

• chr19-7535971-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001166114.2(PNPLA6):​c.183G>A​(p.Val61Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00781 in 1,581,270 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (101 hom.)
• Consequence: PNPLA6 NM_001166114.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.992

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]

ENSG00000268614 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 19-7535971-G-A is Benign according to our data. Variant chr19-7535971-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 330512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.992 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA6	NM_001166114.2	c.183G>A	p.Val61Val	synonymous_variant	1/32	ENST00000600737.6	NP_001159586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA6	ENST00000600737.6	c.183G>A	p.Val61Val	synonymous_variant	1/32	1	NM_001166114.2	ENSP00000473211.1
ENSG00000268614	ENST00000601870.1	n.*479G>A		non_coding_transcript_exon_variant	7/10	4		ENSP00000471492.1
ENSG00000268614	ENST00000601870.1	n.*479G>A		3_prime_UTR_variant	7/10	4		ENSP00000471492.1

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2842 AN: 152114 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00515

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00849 AC: 1660 AN: 195420 Hom.: 27 AF XY: 0.00752 AC XY: 793 AN XY: 105426

Gnomad AFR exome AF: 0.0554

Gnomad AMR exome AF: 0.00735

Gnomad ASJ exome AF: 0.0245

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00119

Gnomad FIN exome AF: 0.000978

Gnomad NFE exome AF: 0.00519

Gnomad OTH exome AF: 0.00881

GnomAD4 exome AF: 0.00666 AC: 9511 AN: 1429038 Hom.: 101 Cov.: 32 AF XY: 0.00640 AC XY: 4532 AN XY: 708616

Gnomad4 AFR exome AF: 0.0574

Gnomad4 AMR exome AF: 0.00818

Gnomad4 ASJ exome AF: 0.0237

Gnomad4 EAS exome AF: 0.0000518

Gnomad4 SAS exome AF: 0.000969

Gnomad4 FIN exome AF: 0.00138

Gnomad4 NFE exome AF: 0.00531

Gnomad4 OTH exome AF: 0.00913

GnomAD4 genome AF: 0.0187 AC: 2845 AN: 152232 Hom.: 71 Cov.: 32 AF XY: 0.0178 AC XY: 1326 AN XY: 74434

Gnomad4 AFR AF: 0.0531

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00515

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0136 Hom.: 16

Bravo AF: 0.0219

Asia WGS AF: 0.00549 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2017	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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Mucolipidosis type IV Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 27, 2021

- -

Spastic Paraplegia, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35732838; hg19: chr19-7600857;