19-7535117-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000450331.7(PNPLA6):c.-118-10A>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 282,348 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0055 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (2 hom.)
• Consequence: PNPLA6 ENST00000450331.7 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.005729
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0340

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-7535117-A-T is Benign according to our data. Variant chr19-7535117-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 1700443.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00553 (841/152206) while in subpopulation AFR AF= 0.0192 (799/41534). AF 95% confidence interval is 0.0181. There are 8 homozygotes in gnomad4. There are 400 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA6	NM_001166111.2	c.-43+215A>T		intron_variant
PNPLA6	NM_001166112.2	c.-43+215A>T		intron_variant
PNPLA6	NM_001166113.1	c.-118-10A>T		splice_polypyrimidine_tract_variant, intron_variant
PNPLA6	NM_006702.5	c.-43+215A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA6	ENST00000221249.10	c.-43+215A>T		intron_variant		1		A1
PNPLA6	ENST00000450331.7	c.-118-10A>T		splice_polypyrimidine_tract_variant, intron_variant		1		A1
PNPLA6	ENST00000593924.5	c.-139A>T		5_prime_UTR_variant	1/6	4

Frequencies

GnomAD3 genomes AF: 0.00552 AC: 840 AN: 152088 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000822 AC: 107 AN: 130142 Hom.: 2 Cov.: 0 AF XY: 0.000640 AC XY: 44 AN XY: 68748

Gnomad4 AFR exome AF: 0.0184

Gnomad4 AMR exome AF: 0.000940

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: 0.0000135

Gnomad4 OTH exome AF: 0.000880

GnomAD4 genome AF: 0.00553 AC: 841 AN: 152206 Hom.: 8 Cov.: 32 AF XY: 0.00538 AC XY: 400 AN XY: 74414

Gnomad4 AFR AF: 0.0192

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00388 Hom.: 0

Bravo AF: 0.00625

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 08, 2022

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	8.8
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0057
dbscSNV1_RF	Benign	0.026
SpliceAI score (max)		0.14		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: rs112541066; hg19: chr19-7600003;