rs387906638

Positions:

• chr2-69374078-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP2 PP5 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 Pathogenic (no stars). 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: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.82

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a strand (size 12) in uniprot entity GFPT1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) 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 id is 1067128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, GFPT1
• PP5: Variant 2-69374078-T-C is Pathogenic according to our data. Variant chr2-69374078-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 29739.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-69374078-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3790905). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFPT1	NM_001244710.2	c.43A>G	p.Thr15Ala	missense_variant	2/20	ENST00000357308.9
GFPT1	NM_002056.4	c.43A>G	p.Thr15Ala	missense_variant	2/19
GFPT1	XM_017003801.2	c.118A>G	p.Thr40Ala	missense_variant	2/20
GFPT1	XM_017003802.3	c.118A>G	p.Thr40Ala	missense_variant	2/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFPT1	ENST00000357308.9	c.43A>G	p.Thr15Ala	missense_variant	2/20	5	NM_001244710.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital myasthenic syndrome 12 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 11, 2011

- -

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
MutationTaster	Benign	1.0	D;D
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

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

Other links and lift over

dbSNP: rs387906638; hg19: chr2-69601210;