rs1011196447

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_001244710.2(GFPT1):c.686-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000113 in 1,589,450 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

GFPT1
NM_001244710.2 splice_acceptor, intron

Scores

Splicing: ADA: 0.9434

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 4.94

Publications

1 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), PanelApp Australia, Ambry Genetics, 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.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.025714286 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.7, offset of 4, new splice context is: tgttgtgtatccttggctAGgac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP5

Variant 2-69354314-T-C is Pathogenic according to our data. Variant chr2-69354314-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 540353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GFPT1	NM_001244710.2 link	c.686-2A>G	splice_acceptor_variant, intron_variant	Intron 8 of 19	ENST00000357308.9	NP_001231639.1	Q06210-1
GFPT1	NM_002056.4 link	c.685+175A>G	intron_variant	Intron 8 of 18		NP_002047.2	Q06210-2
GFPT1	XM_017003801.2 link	c.761-2A>G	splice_acceptor_variant, intron_variant	Intron 8 of 19		XP_016859290.1
GFPT1	XM_017003802.3 link	c.760+175A>G	intron_variant	Intron 8 of 18		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GFPT1	ENST00000357308.9 link	c.686-2A>G	splice_acceptor_variant, intron_variant	Intron 8 of 19	5	NM_001244710.2	ENSP00000349860.4	Q06210-1
GFPT1	ENST00000361060.5 link	c.685+175A>G	intron_variant	Intron 8 of 18	1		ENSP00000354347.4	Q06210-2
GFPT1	ENST00000674507.1 link	c.685+175A>G	intron_variant	Intron 8 of 17			ENSP00000501332.1	A0A6I8PTT9
GFPT1	ENST00000674438.1 link	c.469+175A>G	intron_variant	Intron 6 of 16			ENSP00000501469.1	A0A6I8PRN4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000227

AC:

AN:

219992

AF XY:

0.0000332

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000992

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1437246

Hom.:

Cov.:

AF XY:

0.0000126

AC XY:

AN XY:

714752

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33296

American (AMR)

AF:

0.000206

AC:

AN:

43662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25850

East Asian (EAS)

AF:

0.00

AC:

AN:

39514

South Asian (SAS)

AF:

0.00

AC:

AN:

84888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38860

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1105454

Other (OTH)

AF:

0.0000500

AC:

AN:

59980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.000131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 12

Pathogenic:5

Jan 03, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000540353). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000024, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID:23794683, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects an acceptor splice site in intron 8 of the GFPT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (no rsID available, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with congenital myasthenic syndrome (PMID: 23794683, 28464723, 29054425). ClinVar contains an entry for this variant (Variation ID: 540353). Studies have shown that disruption of this splice site results in deletion of the first 4 nucleotides of the muscle-specific exon of GFPT1, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 23794683). For these reasons, this variant has been classified as Pathogenic. -

Oct 04, 2021

Pars Genome Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 15, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The homozygous c.686-2A>G variant in GFPT1 was identified by our study in one individual with congenital myasthenic syndrome. The c.686-2A>G variant in GFPT1 has been previously reported in at least four unrelated individuals with congenital myasthenic syndrome 12 (PMID: 28464723, PMID: 29054425, PMID: 32403337, PMID: 32528171, PMID: 23794683) but has been identified in 0.015% (5/33776) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs772941684). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 540353) and has been interpreted as pathogenic by Invitae, Illumina, 3billion, Pars Genome Lab, and Kariminejad - Najmabadi Pathology & Genetics Center. Of these four individuals with congenital myasthenic syndrome 12 (PMID: 28464723, PMID: 29054425, PMID: 32403337, PMID: 32528171, PMID: 23794683), three were homozygotes (PMID: 28464723, PMID: 29054425, PMID: 32403337, PMID: 32528171) and one was a compound heterozygote who carried a likely pathogenic variant in trans (PMID: 23794683, ClinVar Variation ID: 859066), which increases the likelihood that the c.686-2A>G variant is pathogenic. RT-PCR and cDNA analysis of patient muscle tissue showed that the c.686-2A>G variant resulted in a 4 base-pair deletion of the muscle-specific exon of GFPT1, leading to frameshift and a premature stop codon 56 amino acids downstream (PMID: 23794683). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the GFPT1 gene is strongly associated to autosomal recessive congenital myasthenic syndrome 12. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive congenital myasthenic syndrome 12. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PS3_Supporting (Richards 2015). -

GFPT1-related myasthenic syndrome

Pathogenic:1

Jan 04, 2022

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GFPT1 c.686-2A>G variant results in the substitution of an adenine within the consensus splice acceptor site with a guanine, which may result in splicing defects. Across a selection of the available literature, this variant has been identified in at least five individuals with a congenital myasthenic syndrome or limb-girdle muscle weakness, including in a confirmed or presumed homozygous state in four individuals, and in a compound heterozygous state in one individual (Selcen et al. 2013; Yiş et al. 2017; Natera-de Benito et al. 2017; Gonzalez-Quereda et al. 2020; Töpf et al. 2020). The highest frequency of this allele in the Genome Aggregation Database is 0.000148 in the Latino/Admixed American population (version 2.1.1). This variant precedes the muscle-specific exon of GFPT1, and patient cDNA studies have shown that it eliminates the first four nucleotides of this exon and results in missense changes of 56 amino acids and a premature stop codon (Selcen et al. 2013). This variant was identified in a homozygous state. Based on the available evidence, the c.686-2A>G variant is classified as pathogenic for GFPT1-related myasthenic syndrome. -

GFPT1-related disorder

Pathogenic:1

May 10, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GFPT1 c.686-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with congenital myasthenic syndrome (see for example, Selcen et al. 2013. PubMed ID: 23794683; Yiş U et al. 2017. PubMed ID: 28464723; Natera-de Benito et al. 2017. PubMed ID: 29054425). In vitro functional study suggests this variant impacts protein function (Patient 6 in Figure 3, Selcen et al. 2013. PubMed ID: 23794683). This variant is reported in 0.015% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-69581446-T-C). Variants that disrupt the consensus splice acceptor site in GFPT1 are expected to be pathogenic. This variant is interpreted as pathogenic.. -

Congenital myasthenic syndrome 4C;C3552335:Congenital myasthenic syndrome 12

Pathogenic:1

May 12, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GFPT1: PVS1, PM3, PM2:Supporting, PS3:Supporting -

Abnormality of the musculature

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.94

PhyloP100

4.9

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Pathogenic

0.80

SpliceAI score (max)

0.070

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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rs1011196447

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over