rs112732576

chr19-7535969-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001166114.2(PNPLA6):c.181G>C(p.Val61Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,582,828 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V61V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (41 hom.)
• Consequence: PNPLA6 NM_001166114.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0250

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PNPLA6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0018042326).
• BP6: Variant 19-7535969-G-C is Benign according to our data. Variant chr19-7535969-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 240703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0121 (1846/152290) while in subpopulation AFR AF= 0.0428 (1779/41552). AF 95% confidence interval is 0.0412. There are 41 homozygotes in gnomad4. There are 860 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA6	NM_001166114.2	c.181G>C	p.Val61Leu	missense_variant	1/32	ENST00000600737.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA6	ENST00000600737.6	c.181G>C	p.Val61Leu	missense_variant	1/32	1	NM_001166114.2	P3

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1839 AN: 152172 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00299 AC: 590 AN: 197048 Hom.: 12 AF XY: 0.00208 AC XY: 221 AN XY: 106378

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000153

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000693

Gnomad OTH exome AF: 0.000992

GnomAD4 exome AF: 0.00119 AC: 1696 AN: 1430538 Hom.: 41 Cov.: 32 AF XY: 0.00106 AC XY: 749 AN XY: 709466

Gnomad4 AFR exome AF: 0.0426

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000157

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000200

Gnomad4 OTH exome AF: 0.00249

GnomAD4 genome AF: 0.0121 AC: 1846 AN: 152290 Hom.: 41 Cov.: 32 AF XY: 0.0116 AC XY: 860 AN XY: 74454

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00410 Hom.: 7

Bravo AF: 0.0138

ESP6500AA AF: 0.0449 AC: 197

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00339 AC: 406

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 39 Benign:2

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 29, 2020

- -

Mucolipidosis type IV Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Laurence-Moon syndrome;C1848745:Trichomegaly-retina pigmentary degeneration-dwarfism syndrome;C1859093:Ataxia-hypogonadism-choroidal dystrophy syndrome;C2677586:Hereditary spastic paraplegia 39 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 13, 2022

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 07, 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	7.9
Dann	Benign	0.71
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.78	N;N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.15	N;.;.;N;.;N;N;.;.;.
REVEL	Benign	0.032
Sift	Benign	1.0	T;.;.;T;.;T;T;.;.;.
Sift4G	Benign	0.65	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;.;B;.;.;.
Vest4		0.15
MutPred		0.33		.;.;.;.;.;.;.;.;.;Loss of sheet (P = 0.007);
MVP		0.081
MPC		1.1
ClinPred		0.0021	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.48

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: rs112732576; hg19: chr19-7600855;