2-69354314-T-C

Position:

chr2-69354314-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_001244710.2(GFPT1):c.686-2A>G variant causes a splice acceptor 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

Scores

Splicing: ADA: 0.9434

Clinical Significance

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

Conservation

PhyloP100: 4.94

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.025238095 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.

PM2

Very rare variant in population databases, with high coverage;

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. Variant chr2-69354314-T-C is described in Lovd as [Likely_pathogenic]. Variant chr2-69354314-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
GFPT1	NM_001244710.2 linkuse as main transcript	c.686-2A>G	splice_acceptor_variant	ENST00000357308.9	NP_001231639.1
GFPT1	XM_017003801.2 linkuse as main transcript	c.761-2A>G	splice_acceptor_variant		XP_016859290.1
GFPT1	NM_002056.4 linkuse as main transcript	c.685+175A>G	intron_variant		NP_002047.2
GFPT1	XM_017003802.3 linkuse as main transcript	c.760+175A>G	intron_variant		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9 linkuse as main transcript	c.686-2A>G	splice_acceptor_variant	5	NM_001244710.2	ENSP00000349860		Q06210-1
GFPT1	ENST00000361060.5 linkuse as main transcript	c.685+175A>G	intron_variant	1		ENSP00000354347	P1	Q06210-2
GFPT1	ENST00000674438.1 linkuse as main transcript	c.469+175A>G	intron_variant			ENSP00000501469
GFPT1	ENST00000674507.1 linkuse as main transcript	c.685+175A>G	intron_variant			ENSP00000501332

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

GnomAD3 exomes

AF:

0.0000227

AC:

AN:

219992

Hom.:

AF XY:

0.0000332

AC XY:

AN XY:

120432

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000206

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:

0.00000181

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	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 disrupted 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 introduces a premature termination codon (PMID: 23794683). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 15, 2023	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Pars Genome Lab	Oct 04, 2021	- -

GFPT1-related myasthenic syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 04, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2022

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

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

Abnormality of the musculature

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.94

MutationTaster

Benign

1.0

D;D

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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