6-109691254-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000675726.1(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 ENST00000675726.1 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.721

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]

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]

ACMG classification

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 GnomAd at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FIG4	NM_014845.6			upstream_gene_variant		ENST00000230124.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FIG4	ENST00000230124.8			upstream_gene_variant		1	NM_014845.6	P4

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1810 AN: 152162 Hom.: 14 Cov.: 32

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.: 75 Cov.: 5 AF XY: 0.0136 AC XY: 3518 AN XY: 259562

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.: 14 Cov.: 32 AF XY: 0.0114 AC XY: 852 AN XY: 74460

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.: 4

Bravo AF: 0.0120

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	13
Dann	Benign	0.94

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55873083; hg19: chr6-110012457;