rs201322234

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PM5PP2PP5_Very_StrongBP4

The NM_001244710.2(GFPT1):c.331C>T(p.Arg111Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R111H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

GFPT1
NM_001244710.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.41

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 12
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Illumina
congenital myasthenic syndromes with glycosylation defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

GFPT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-69363562-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1073321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.3482 (above the threshold of 3.09). Trascript score misZ: 4.3487 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital myasthenic syndrome 12, congenital myasthenic syndromes with glycosylation defect.

PP5

Variant 2-69363563-G-A is Pathogenic according to our data. Variant chr2-69363563-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 29735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.41946968). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244710.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFPT1	NM_001244710.2	MANE Select	c.331C>T	p.Arg111Cys	missense	Exon 4 of 20	NP_001231639.1	Q06210-1
	GFPT1	NM_002056.4		c.331C>T	p.Arg111Cys	missense	Exon 4 of 19	NP_002047.2	Q06210-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFPT1	ENST00000357308.9	TSL:5 MANE Select	c.331C>T	p.Arg111Cys	missense	Exon 4 of 20	ENSP00000349860.4	Q06210-1
GFPT1	ENST00000361060.5	TSL:1	c.331C>T	p.Arg111Cys	missense	Exon 4 of 19	ENSP00000354347.4	Q06210-2
GFPT1	ENST00000955842.1		c.331C>T	p.Arg111Cys	missense	Exon 4 of 21	ENSP00000625901.1

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000139

AC:

AN:

251416

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1111888

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000296

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41524

American (AMR)

AF:

0.00262

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000322

Hom.:

Bravo

AF:

0.000291

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital myasthenic syndrome 12 (5)

Congenital myasthenic syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.058

MetaRNN

Benign

0.42

MetaSVM

Uncertain

-0.015

MutationAssessor

Benign

1.8

PhyloP100

1.4

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0090

Sift4G

Benign

0.12

Polyphen

0.71

Vest4

0.71

MVP

0.96

MPC

1.2

ClinPred

0.20

GERP RS

4.4

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.75

gMVP

0.80

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over