rs560849

Variant names:

• chr19-7534174-T-C
• rs560849
• ENST00000221249:c.-261T>C

Variant summary

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

The NM_006702.5(PNPLA6):​c.-261T>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 0.281 in 362,652 control chromosomes in the GnomAD database, including 15,542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7008 hom., cov: 31)
  • Exomes 𝑓: 0.27 (8534 hom.)
• Consequence: PNPLA6 NM_006702.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.121

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:):

MCOLN1 (HGNC:13356): (mucolipin TRP cation channel 1) This gene encodes a memberof the transient receptor potential (TRP) cation channel gene family. The transmembrane protein localizes to intracellular vesicular membranes including lysosomes, and functions in the late endocytic pathway and in the regulation of lysosomal exocytosis. The channel is permeable to Ca(2+), Fe(2+), Na(+), K(+), and H(+), and is modulated by changes in Ca(2+) concentration. Mutations in this gene result in mucolipidosis type IV. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-7534174-T-C is Benign according to our data. Variant chr19-7534174-T-C is described in ClinVar as [Benign]. Clinvar id is 369302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7534174-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNPLA6	NM_006702.5	c.-261T>C		5_prime_UTR_variant	Exon 1 of 35		NP_006693.3
MCOLN1	NM_020533.3	c.*379T>C		downstream_gene_variant		ENST00000264079.11	NP_065394.1
PNPLA6	NM_001166112.2	c.-468T>C		upstream_gene_variant			NP_001159584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000268614	ENST00000601870.1	n.*85T>C		non_coding_transcript_exon_variant	Exon 3 of 10	4		ENSP00000471492.1
ENSG00000268614	ENST00000601870.1	n.*85T>C		3_prime_UTR_variant	Exon 3 of 10	4		ENSP00000471492.1
MCOLN1	ENST00000264079.11	c.*379T>C		downstream_gene_variant		1	NM_020533.3	ENSP00000264079.5

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44985 AN: 151762 Hom.: 6986 Cov.: 31

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.392

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.264

GnomAD4 exome AF: 0.269 AC: 56747 AN: 210772 Hom.: 8534 Cov.: 0 AF XY: 0.267 AC XY: 30256 AN XY: 113322

Gnomad4 AFR exome AF: 0.270

Gnomad4 AMR exome AF: 0.459

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.375

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.296

Gnomad4 NFE exome AF: 0.257

Gnomad4 OTH exome AF: 0.258

GnomAD4 genome AF: 0.297 AC: 45041 AN: 151880 Hom.: 7008 Cov.: 31 AF XY: 0.297 AC XY: 22054 AN XY: 74196

Gnomad4 AFR AF: 0.290

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.167

Gnomad4 EAS AF: 0.393

Gnomad4 SAS AF: 0.277

Gnomad4 FIN AF: 0.314

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.263

Alfa AF: 0.268 Hom.: 5082

Bravo AF: 0.307

Asia WGS AF: 0.354 AC: 1230 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 28, 2022

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: 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	-0.70
CADD	Benign	13
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs560849; hg19: chr19-7599060;