rs548471516

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

Scores

2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -1.02

Publications

0 publications found
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]
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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
FIG4NM_014845.6 linkc.-132A>G 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 23 ENST00000230124.8 NP_055660.1 Q92562
FIG4NM_014845.6 linkc.-132A>G 5_prime_UTR_variant Exon 1 of 23 ENST00000230124.8 NP_055660.1 Q92562
AK9NM_001145128.3 linkc.-169T>C upstream_gene_variant ENST00000424296.7 NP_001138600.2 Q5TCS8-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FIG4ENST00000230124.8 linkc.-132A>G 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 23 1 NM_014845.6 ENSP00000230124.4 Q92562
FIG4ENST00000230124.8 linkc.-132A>G 5_prime_UTR_variant Exon 1 of 23 1 NM_014845.6 ENSP00000230124.4 Q92562
AK9ENST00000424296.7 linkc.-169T>C upstream_gene_variant 5 NM_001145128.3 ENSP00000410186.2 Q5TCS8-4

Frequencies

GnomAD3 genomes
AF:
0.00146
AC:
220
AN:
151034
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
52
104
156
208
260
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00146
AC:
220
AN:
151150
Hom.:
0
Cov.:
32
AF XY:
0.00137
AC XY:
101
AN XY:
73842
show subpopulations
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.512
Heterozygous variant carriers
0
11
23
34
46
57
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
LINK: link

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

Publications

Other links and lift over

dbSNP: rs548471516; hg19: chr6-110012507; API