ENST00000221249:c.-96A>C

Variant names:

• chr19-7534849-A-C
• rs604959
• ENST00000221249:c.-96A>C

Variant summary

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

The ENST00000221249(PNPLA6):​c.-96A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 153,734 control chromosomes in the GnomAD database, including 6,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (5965 hom., cov: 32)
  • Exomes 𝑓: 0.22 (48 hom.)
• Consequence: PNPLA6 ENST00000221249 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.105

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=-0.85).
• BP6: Variant 19-7534849-A-C is Benign according to our data. Variant chr19-7534849-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 330509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7534849-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA6	NM_001166111.2	c.-96A>C		5_prime_UTR_variant	Exon 1 of 34		NP_001159583.1
PNPLA6	NM_001166113.1	c.-172A>C		5_prime_UTR_variant	Exon 1 of 35		NP_001159585.1
PNPLA6	NM_006702.5	c.-96A>C		5_prime_UTR_variant	Exon 2 of 35		NP_006693.3
PNPLA6	NM_001166112.2	c.-96A>C		5_prime_UTR_variant	Exon 2 of 34		NP_001159584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000268614	ENST00000601870.1	n.*318A>C		non_coding_transcript_exon_variant	Exon 5 of 10	4		ENSP00000471492.1
ENSG00000268614	ENST00000601870.1	n.*318A>C		3_prime_UTR_variant	Exon 5 of 10	4		ENSP00000471492.1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42098 AN: 151914 Hom.: 5945 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.216 AC: 367 AN: 1702 Hom.: 48 Cov.: 0 AF XY: 0.209 AC XY: 203 AN XY: 972

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.259

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.0833

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.278

GnomAD4 genome AF: 0.277 AC: 42153 AN: 152032 Hom.: 5965 Cov.: 32 AF XY: 0.275 AC XY: 20430 AN XY: 74320

Gnomad4 AFR AF: 0.285

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.291

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.240

Alfa AF: 0.268 Hom.: 11189

Bravo AF: 0.278

Asia WGS AF: 0.294 AC: 1021 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucolipidosis type IV Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic Paraplegia, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 39 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.8
DANN	Benign	0.57

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: rs604959; hg19: chr19-7599735;