rs368208403

Positions:

chr2-69327007-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001244710.2(GFPT1):c.1962G>C(p.Lys654Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GFPT1
NM_001244710.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.0610

Variant links:

Genes affected

GFPT1 (HGNC:4241): (glutamine--fructose-6-phosphate transaminase 1) This gene encodes the first and rate-limiting enzyme of the hexosamine pathway and controls the flux of glucose into the hexosamine pathway. The product of this gene catalyzes the formation of glucosamine 6-phosphate. [provided by RefSeq, Sep 2008]

GFPT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GFPT1. . Gene score misZ 4.3482 (greater than the threshold 3.09). Trascript score misZ 4.3487 (greater than threshold 3.09). GenCC has associacion of gene with congenital myasthenic syndromes with glycosylation defect, congenital myasthenic syndrome 12.

BP4

Computational evidence support a benign effect (MetaRNN=0.29566282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GFPT1	NM_001244710.2 linkuse as main transcript	c.1962G>C	p.Lys654Asn	missense_variant	19/20	ENST00000357308.9
GFPT1	NM_002056.4 linkuse as main transcript	c.1908G>C	p.Lys636Asn	missense_variant	18/19
GFPT1	XM_017003801.2 linkuse as main transcript	c.2037G>C	p.Lys679Asn	missense_variant	19/20
GFPT1	XM_017003802.3 linkuse as main transcript	c.1983G>C	p.Lys661Asn	missense_variant	18/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFPT1	ENST00000357308.9 linkuse as main transcript	c.1962G>C	p.Lys654Asn	missense_variant	19/20	5	NM_001244710.2		Q06210-1
GFPT1	ENST00000361060.5 linkuse as main transcript	c.1908G>C	p.Lys636Asn	missense_variant	18/19	1		P1	Q06210-2
GFPT1	ENST00000674507.1 linkuse as main transcript	c.1740G>C	p.Lys580Asn	missense_variant	17/18
GFPT1	ENST00000674438.1 linkuse as main transcript	c.1692G>C	p.Lys564Asn	missense_variant	16/17

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.1908G>C (p.K636N) alteration is located in coding exon 18 of the GFPT1 gene. This alteration results from a G to C substitution at nucleotide position 1908, causing the lysine (K) at amino acid position 636 to be replaced by an asparagine (N). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the GFPT1 c.1908G>C alteration was not observed, with coverage at this position. The altered amino acid is not conserved throughout evolution:_x000D_ _x000D_ The p.K636 amino acid is not conserved in available vertebrate species, and asparagine is the reference amino acid in multiple species. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.K636N alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myasthenic syndrome 12

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 04, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GFPT1 protein function. ClinVar contains an entry for this variant (Variation ID: 473131). This missense change has been observed in individual(s) with congenital myasthenic syndrome (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 654 of the GFPT1 protein (p.Lys654Asn). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.057

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.61

N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.14

Sift

Uncertain

0.026

D;D

Sift4G

Benign

0.074

T;T

Polyphen

0.0010

.;B

Vest4

0.33

MutPred

0.51

Loss of methylation at K654 (P = 0.0097);.;

MVP

0.47

MPC

1.3

ClinPred

0.72

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.43

gMVP

0.87

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over