chr19-7534823-G-A

Position:

• chr19-7534823-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000221249.10(PNPLA6):​c.-122G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 154,140 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (0 hom.)
• Consequence: PNPLA6 ENST00000221249.10 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0580

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00406 (619/152284) while in subpopulation NFE AF= 0.0066 (449/68038). AF 95% confidence interval is 0.00609. There are 2 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA6	NM_001166111.2	c.-122G>A		5_prime_UTR_variant	1/34		NP_001159583.1
PNPLA6	NM_001166112.2	c.-122G>A		5_prime_UTR_variant	2/34		NP_001159584.1
PNPLA6	NM_001166113.1	c.-198G>A		5_prime_UTR_variant	1/35		NP_001159585.1
PNPLA6	NM_006702.5	c.-122G>A		5_prime_UTR_variant	2/35		NP_006693.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNPLA6	ENST00000221249.10	c.-122G>A		5_prime_UTR_variant	2/35	1		ENSP00000221249	A1
PNPLA6	ENST00000450331.7	c.-198G>A		5_prime_UTR_variant	1/35	1		ENSP00000394348	A1
PNPLA6	ENST00000414982.7	c.-122G>A		5_prime_UTR_variant	1/34	2		ENSP00000407509

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 620 AN: 152166 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00661

Gnomad OTH AF: 0.00670

GnomAD4 exome AF: 0.00539 AC: 10 AN: 1856 Hom.: 0 Cov.: 0 AF XY: 0.00569 AC XY: 6 AN XY: 1054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00758

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00406 AC: 619 AN: 152284 Hom.: 2 Cov.: 32 AF XY: 0.00377 AC XY: 281 AN XY: 74446

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00660

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00542 Hom.: 0

Bravo AF: 0.00427

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 39 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.4
DANN	Benign	0.76

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: rs45483295; hg19: chr19-7599709;