Genetic Variant NM_018291.5:c.314G>C (chr1-59346247-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018291.5(FGGY):c.314G>C(p.Gly105Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,556 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G105E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FGGY
NM_018291.5 missense, splice_region

Scores

Splicing: ADA: 0.02039

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.32

Publications

0 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]

FGGY links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGGY	NM_018291.5 link	c.314G>C	p.Gly105Ala	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
FGGY	ENST00000303721.12 link	c.314G>C	p.Gly105Ala	missense_variant, splice_region_variant	Exon 4 of 16	1	NM_018291.5	ENSP00000305922.8		Q96C11-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460556

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726624

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5194

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111596

Other (OTH)

AF:

0.00

AC:

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.018

T;.;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.081

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.066

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.3

.;M;M

PhyloP100

6.3

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Uncertain

0.47

Sift

Benign

0.054

T;D;D

Sift4G

Benign

0.091

T;T;T

Polyphen

0.98, 0.96

.;D;D

Vest4

0.57, 0.56

MutPred

0.60

Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);

MVP

0.39

MPC

0.073

ClinPred

0.97

GERP RS

4.6

Varity_R

0.36

gMVP

0.65

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.020

dbscSNV1_RF

Benign

0.37

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: -48

DS_AL_spliceai

0.32

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over