chr1-59346351-G-C

Variant names:

• chr1-59346351-G-C
• rs761896156
• NM_018291.5:c.418G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018291.5(FGGY):​c.418G>C​(p.Val140Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FGGY NM_018291.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17028028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGGY	NM_018291.5	c.418G>C	p.Val140Leu	missense_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	c.418G>C	p.Val140Leu	missense_variant	Exon 4 of 16	1	NM_018291.5	ENSP00000305922.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250942 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459558 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726088

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.0000224 AC: 1 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4318

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111620

Other (OTH) AF: 0.00 AC: 0 AN: 60188

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.0093	T;.;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	.;M;M
PhyloP100		3.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.84	N;N;N
REVEL	Benign	0.078
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.14, 0.10
MutPred		0.47		Loss of catalytic residue at V140 (P = 0.0859);Loss of catalytic residue at V140 (P = 0.0859);Loss of catalytic residue at V140 (P = 0.0859);
MVP		0.13
MPC		0.025
ClinPred		0.066	T
GERP RS		2.6
Varity_R		0.18
gMVP		0.58
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs761896156; hg19: chr1-59812023;