chr19-7534221-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006702.5(PNPLA6):c.-214C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0076 in 328,042 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 54 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

PNPLA6
NM_006702.5 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0440

Variant links:

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]

PNPLA6 links:

ENSG00000268614 (HGNC:):

ENSG00000268614 links:

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]

MCOLN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 19-7534221-C-T is Benign according to our data. Variant chr19-7534221-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 369303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0146 (2223/152314) while in subpopulation AFR AF= 0.0512 (2127/41560). AF 95% confidence interval is 0.0494. There are 54 homozygotes in gnomad4. There are 1034 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PNPLA6	NM_006702.5 link	c.-214C>T	5_prime_UTR_variant	Exon 1 of 35		NP_006693.3	Q8IY17-2
MCOLN1	NM_020533.3 link	c.*426C>T	downstream_gene_variant		ENST00000264079.11	NP_065394.1	Q9GZU1
PNPLA6	NM_001166112.2 link	c.-421C>T	upstream_gene_variant			NP_001159584.1	Q8IY17-5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENSG00000268614	ENST00000601870.1 link	n.*132C>T	non_coding_transcript_exon_variant	Exon 3 of 10	4		ENSP00000471492.1	M0R0W3
ENSG00000268614	ENST00000601870.1 link	n.*132C>T	3_prime_UTR_variant	Exon 3 of 10	4		ENSP00000471492.1	M0R0W3
MCOLN1	ENST00000264079.11 link	c.*426C>T	downstream_gene_variant		1	NM_020533.3	ENSP00000264079.5	Q9GZU1

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2212

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0510

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00669

GnomAD4 exome

AF:

0.00153

AC:

269

AN:

175728

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

113

AN XY:

95028

show subpopulations

Gnomad4 AFR exome

AF:

0.0427

Gnomad4 AMR exome

AF:

0.00337

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000246

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000966

Gnomad4 OTH exome

AF:

0.00171

GnomAD4 genome

AF:

0.0146

AC:

2223

AN:

152314

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1034

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0512

Gnomad4 AMR

AF:

0.00425

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.0162

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

Hereditary spastic paraplegia 39

Benign:1

Jan 12, 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

DANN

Benign

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over