chr6-109691254-G-A

Variant names:

Variant summary

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

The ENST00000675726(FIG4):c.-182G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 642,570 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 14 hom., cov: 32)

Exomes 𝑓: 0.014 ( 75 hom. )

Consequence

FIG4
ENST00000675726 5_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.721

Variant links:

Genes affected

FIG4 (HGNC:16873): (FIG4 phosphoinositide 5-phosphatase) The protein encoded by this gene belongs to the SAC domain-containing protein gene family. The SAC domain, approximately 400 amino acids in length and consisting of seven conserved motifs, has been shown to possess phosphoinositide phosphatase activity. The yeast homolog, Sac1p, is involved in the regulation of various phosphoinositides, and affects diverse cellular functions such as actin cytoskeleton organization, Golgi function, and maintenance of vacuole morphology. Membrane-bound phosphoinositides function as signaling molecules and play a key role in vesicle trafficking in eukaryotic cells. Mutations in this gene have been associated with Charcot-Marie-Tooth disease, type 4J. [provided by RefSeq, Jul 2008]

FIG4 links:

AK9 (HGNC:33814): (adenylate kinase 9) The protein encoded by this gene catalyzes the interconversion of nucleosides, possessing both nucleoside monophosphate and diphosphate kinase activities. The encoded protein uses these interconversions to maintain nucleoside homeostasis. [provided by RefSeq, Jul 2016]

AK9 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=-0.82).

BP6

Variant 6-109691254-G-A is Benign according to our data. Variant chr6-109691254-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 355024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1811/152280) while in subpopulation NFE AF= 0.0174 (1185/67994). AF 95% confidence interval is 0.0166. There are 14 homozygotes in gnomad4. There are 852 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK9	NM_001145128.3 link	c.-119C>T		upstream_gene_variant		ENST00000424296.7	NP_001138600.2	Q5TCS8-4
FIG4	NM_014845.6 link	c.-182G>A		upstream_gene_variant		ENST00000230124.8	NP_055660.1	Q92562

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AK9	ENST00000424296.7 link	c.-119C>T		upstream_gene_variant		5	NM_001145128.3	ENSP00000410186.2		Q5TCS8-4
FIG4	ENST00000230124.8 link	c.-182G>A		upstream_gene_variant		1	NM_014845.6	ENSP00000230124.4		Q92562

Frequencies

GnomAD3 genomes

AF:

0.0119

AC:

1810

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00297

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.0156

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0174

Gnomad OTH

AF:

0.0177

GnomAD4 exome

AF:

0.0141

AC:

6920

AN:

490290

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

3518

AN XY:

259562

show subpopulations

Gnomad4 AFR exome

AF:

0.00363

Gnomad4 AMR exome

AF:

0.0121

Gnomad4 ASJ exome

AF:

0.0171

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00417

Gnomad4 FIN exome

AF:

0.0155

Gnomad4 NFE exome

AF:

0.0180

Gnomad4 OTH exome

AF:

0.0134

GnomAD4 genome

AF:

0.0119

AC:

1811

AN:

152280

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

852

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00296

Gnomad4 AMR

AF:

0.0133

Gnomad4 ASJ

AF:

0.0159

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00372

Gnomad4 FIN

AF:

0.0156

Gnomad4 NFE

AF:

0.0174

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.0155

Hom.:

Bravo

AF:

0.0120

Asia WGS

AF:

0.00173

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Likely 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. -

Amyotrophic lateral sclerosis type 11

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. -

Charcot-Marie-Tooth disease type 4J

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Benign

0.94

Splicing

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