rs548471516

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 0 publications found

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]

AK9 Gene-Disease associations (from GenCC):

• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -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	ENST00000230124.8	c.-132A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 23	1	NM_014845.6	ENSP00000230124.4
FIG4	ENST00000230124.8	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

African (AFR) AF: 0.000365 AC: 6 AN: 16428

American (AMR) AF: 0.000412 AC: 14 AN: 33986

Ashkenazi Jewish (ASJ) AF: 0.000761 AC: 15 AN: 19708

East Asian (EAS) AF: 0.0000627 AC: 2 AN: 31900

South Asian (SAS) AF: 0.00191 AC: 120 AN: 62932

European-Finnish (FIN) AF: 0.000119 AC: 5 AN: 42050

Middle Eastern (MID) AF: 0.00291 AC: 12 AN: 4128

European-Non Finnish (NFE) AF: 0.00220 AC: 789 AN: 359098

Other (OTH) AF: 0.00136 AC: 43 AN: 31720

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

African (AFR) AF: 0.000243 AC: 10 AN: 41146

American (AMR) AF: 0.000328 AC: 5 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5060

South Asian (SAS) AF: 0.00147 AC: 7 AN: 4776

European-Finnish (FIN) AF: 0.0000955 AC: 1 AN: 10474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00229 AC: 155 AN: 67720

Other (OTH) AF: 0.00191 AC: 4 AN: 2096

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
PhyloP100		-1.0
PromoterAI		0.049	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs548471516; hg19: chr6-110012507;