6-109691304-A-G

Variant names:

• chr6-109691304-A-G
• rs548471516
• NM_014845.6:c.-132A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014845.6(FIG4):​c.-132A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 753,100 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (1 hom.)
• Consequence: FIG4 NM_014845.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -1.02

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIG4	NM_014845.6	c.-132A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 23	ENST00000230124.8	NP_055660.1
FIG4	NM_014845.6	c.-132A>G		5_prime_UTR_variant	Exon 1 of 23	ENST00000230124.8	NP_055660.1
AK9	NM_001145128.3	c.-169T>C		upstream_gene_variant		ENST00000424296.7	NP_001138600.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124	c.-132A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 23	1	NM_014845.6	ENSP00000230124.4
FIG4	ENST00000230124	c.-132A>G		5_prime_UTR_variant	Exon 1 of 23	1	NM_014845.6	ENSP00000230124.4
AK9	ENST00000424296.7	c.-169T>C		upstream_gene_variant		5	NM_001145128.3	ENSP00000410186.2

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 220 AN: 151034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000244

Gnomad AMI AF: 0.0398

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.0000955

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00193

GnomAD4 exome AF: 0.00167 AC: 1006 AN: 601950 Hom.: 1 Cov.: 8 AF XY: 0.00170 AC XY: 548 AN XY: 321764

Gnomad4 AFR exome AF: 0.000365

Gnomad4 AMR exome AF: 0.000412

Gnomad4 ASJ exome AF: 0.000761

Gnomad4 EAS exome AF: 0.0000627

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.000119

Gnomad4 NFE exome AF: 0.00220

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00146 AC: 220 AN: 151150 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 101 AN XY: 73842

Gnomad4 AFR AF: 0.000243

Gnomad4 AMR AF: 0.000328

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00147

Gnomad4 FIN AF: 0.0000955

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00148

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 11 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Charcot-Marie-Tooth disease type 4J Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.30
DANN	Benign	0.46

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs548471516; hg19: chr6-110012507;