rs387906638

Variant names:

• chr2-69374078-T-C
• rs387906638
• NM_001244710.2:c.43A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP2 BP4

The NM_001244710.2(GFPT1):​c.43A>G​(p.Thr15Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,443,362 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T15M) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GFPT1 NM_001244710.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 4.82
• Publications: 3 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001244710.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-69374077-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1067128.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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3790905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFPT1	NM_001244710.2	c.43A>G	p.Thr15Ala	missense_variant	Exon 2 of 20	ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4	c.43A>G	p.Thr15Ala	missense_variant	Exon 2 of 19		NP_002047.2
GFPT1	XM_017003801.2	c.118A>G	p.Thr40Ala	missense_variant	Exon 2 of 20		XP_016859290.1
GFPT1	XM_017003802.3	c.118A>G	p.Thr40Ala	missense_variant	Exon 2 of 19		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9	c.43A>G	p.Thr15Ala	missense_variant	Exon 2 of 20	5	NM_001244710.2	ENSP00000349860.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1443362 Hom.: 0 Cov.: 25 AF XY: 0.00000139 AC XY: 1 AN XY: 719168

African (AFR) AF: 0.00 AC: 0 AN: 33110

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39416

South Asian (SAS) AF: 0.00 AC: 0 AN: 85704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096070

Other (OTH) AF: 0.00 AC: 0 AN: 59612

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 12 Pathogenic:1 Uncertain:1

Feb 11, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 15 of the GFPT1 protein (p.Thr15Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 21310273). ClinVar contains an entry for this variant (Variation ID: 29739). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects GFPT1 function (PMID: 21310273). This variant disrupts the p.Thr15 amino acid residue in GFPT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21310273, 23569079, 23794683, 28712002; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

not specified Uncertain:1

Jul 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GFPT1 c.43A>G (p.Thr15Ala) results in a non-conservative amino acid change located in the Glutamine amidotransferase type 2 domain (IPR017932) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251206 control chromosomes. c.43A>G has been reported in the literature in at least one compound heterozygous individual affected with Congenital Myasthenic Syndrome (Senderek_2011, Guergueltcheva_2012). These data do not allow any conclusion about variant significance. A different variant affecting the same codon has been classified as pathogenic by our lab (c.44C>T, p.Thr15Met), supporting the critical relevance of codon 15 to GFPT1 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >60% of normal glutamine-fructose-6-phosphate transaminase 1 activity in transfected cells (Senderek_2011). The following publications have been ascertained in the context of this evaluation (PMID: 21975507, 21310273). ClinVar contains an entry for this variant (Variation ID: 29739). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L;L
PhyloP100		4.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.095
Sift	Benign	0.14	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.51	.;P
Vest4		0.59
MutPred		0.43		Loss of phosphorylation at T15 (P = 0.0343);Loss of phosphorylation at T15 (P = 0.0343);
MVP		0.47
MPC		0.84
ClinPred		0.86	D
GERP RS		5.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.27
gMVP		0.82
Mutation Taster		=12/88	disease causing (ClinVar)

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: rs387906638; hg19: chr2-69601210;