chr1-59346397-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_018291.5(FGGY):​c.464A>G​(p.Glu155Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,611,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E155K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

FGGY
NM_018291.5 missense, splice_region

Scores

5
10
4
Splicing: ADA: 0.9947
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.12

Publications

1 publications found
Variant links:
Genes affected
FGGY (HGNC:25610): (FGGY carbohydrate kinase domain containing) This gene encodes a protein that phosphorylates carbohydrates such as ribulose, ribitol, and L-arabinitol. Genome-wide association studies in some populations have found an association between polymorphisms in this gene and sporadic amyotrophic lateral sclerosis, but studies of other populations have not been able to replicate this association. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FGGYNM_018291.5 linkc.464A>G p.Glu155Gly missense_variant, splice_region_variant Exon 4 of 16 ENST00000303721.12 NP_060761.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FGGYENST00000303721.12 linkc.464A>G p.Glu155Gly missense_variant, splice_region_variant Exon 4 of 16 1 NM_018291.5 ENSP00000305922.8 Q96C11-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152106
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000280
AC:
7
AN:
250380
AF XY:
0.0000148
show subpopulations
Gnomad AFR exome
AF:
0.000370
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000754
AC:
11
AN:
1459036
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
725804
show subpopulations
African (AFR)
AF:
0.000210
AC:
7
AN:
33358
American (AMR)
AF:
0.00
AC:
0
AN:
44664
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26098
East Asian (EAS)
AF:
0.000101
AC:
4
AN:
39688
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86134
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53386
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4136
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111410
Other (OTH)
AF:
0.00
AC:
0
AN:
60162
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000526
AC:
8
AN:
152106
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74298
show subpopulations
African (AFR)
AF:
0.000169
AC:
7
AN:
41414
American (AMR)
AF:
0.00
AC:
0
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68006
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.412
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000132
Hom.:
0
Bravo
AF:
0.0000680
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 23, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.464A>G (p.E155G) alteration is located in exon 4 (coding exon 3) of the FGGY gene. This alteration results from a A to G substitution at nucleotide position 464, causing the glutamic acid (E) at amino acid position 155 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Uncertain
0.070
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Benign
0.066
T;.;T
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Benign
0.73
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Pathogenic
0.77
D;D;D
MetaSVM
Benign
-0.32
T
MutationAssessor
Uncertain
2.9
.;M;M
PhyloP100
8.1
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-4.2
D;D;D
REVEL
Uncertain
0.59
Sift
Uncertain
0.0060
D;D;D
Sift4G
Uncertain
0.023
D;D;D
Polyphen
0.89, 0.87
.;P;P
Vest4
0.85, 0.85
MVP
0.75
MPC
0.20
ClinPred
0.74
D
GERP RS
5.5
Varity_R
0.86
gMVP
0.71
Mutation Taster
=35/65
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.90
SpliceAI score (max)
0.24
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.24
Position offset: 1

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

Publications

Other links and lift over

dbSNP: rs754065271; hg19: chr1-59812069; API