19-7535122-T-C

Position:

• chr19-7535122-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001166113.1(PNPLA6):​c.-118-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 339,980 control chromosomes in the GnomAD database, including 531 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (300 hom., cov: 32)
  • Exomes 𝑓: 0.027 (231 hom.)
• Consequence: PNPLA6 NM_001166113.1 splice_region, intron
• Scores: Splicing: ADA: 0.00007304
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.702

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-7535122-T-C is Benign according to our data. Variant chr19-7535122-T-C is described in ClinVar as [Benign]. Clinvar id is 1234448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNPLA6	NM_001166111.2	c.-43+220T>C		intron_variant			NP_001159583.1
PNPLA6	NM_001166113.1	c.-118-5T>C		splice_region_variant, intron_variant			NP_001159585.1
PNPLA6	NM_006702.5	c.-43+220T>C		intron_variant			NP_006693.3
PNPLA6	NM_001166112.2	c.-43+220T>C		intron_variant			NP_001159584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000268614	ENST00000601870.1	n.*371+220T>C		intron_variant		4		ENSP00000471492.1

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5855 AN: 152044 Hom.: 299 Cov.: 32

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0999

Gnomad SAS AF: 0.0464

Gnomad FIN AF: 0.00830

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00616

Gnomad OTH AF: 0.0412

GnomAD4 exome AF: 0.0268 AC: 5037 AN: 187818 Hom.: 231 Cov.: 0 AF XY: 0.0278 AC XY: 2768 AN XY: 99590

Gnomad4 AFR exome AF: 0.0571

Gnomad4 AMR exome AF: 0.166

Gnomad4 ASJ exome AF: 0.0229

Gnomad4 EAS exome AF: 0.0891

Gnomad4 SAS exome AF: 0.0379

Gnomad4 FIN exome AF: 0.00769

Gnomad4 NFE exome AF: 0.00586

Gnomad4 OTH exome AF: 0.0207

GnomAD4 genome AF: 0.0385 AC: 5858 AN: 152162 Hom.: 300 Cov.: 32 AF XY: 0.0409 AC XY: 3043 AN XY: 74384

Gnomad4 AFR AF: 0.0588

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.100

Gnomad4 SAS AF: 0.0462

Gnomad4 FIN AF: 0.00830

Gnomad4 NFE AF: 0.00616

Gnomad4 OTH AF: 0.0403

Alfa AF: 0.0235 Hom.: 18

Bravo AF: 0.0514

Asia WGS AF: 0.0700 AC: 243 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2021	- -
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	-0.90
CADD	Benign	4.0
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000073
dbscSNV1_RF	Benign	0.0
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: rs746130; hg19: chr19-7600008;