2-69346009-T-C

Variant names:

• chr2-69346009-T-C
• rs753072061
• NM_001244710.2:c.1010-10A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001244710.2(GFPT1):​c.1010-10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,422,614 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: GFPT1 NM_001244710.2 intron
• Scores: Splicing: ADA: 0.0003146
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.557
• Publications: 0 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_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-69346009-T-C is Benign according to our data. Variant chr2-69346009-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 473138.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFPT1	NM_001244710.2	MANE Select	c.1010-10A>G		intron	N/A	NP_001231639.1
	GFPT1	NM_002056.4		c.956-10A>G		intron	N/A	NP_002047.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFPT1	ENST00000357308.9	TSL:5 MANE Select	c.1010-10A>G		intron	N/A	ENSP00000349860.4
	GFPT1	ENST00000361060.5	TSL:1	c.956-10A>G		intron	N/A	ENSP00000354347.4
	GFPT1	ENST00000674507.1		c.956-10A>G		intron	N/A	ENSP00000501332.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000520 AC: 13 AN: 249946 AF XY: 0.0000591

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000606 AC: 77 AN: 1270288 Hom.: 0 Cov.: 20 AF XY: 0.0000748 AC XY: 48 AN XY: 641830

African (AFR) AF: 0.00 AC: 0 AN: 29834

American (AMR) AF: 0.00 AC: 0 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24996

East Asian (EAS) AF: 0.00 AC: 0 AN: 38788

South Asian (SAS) AF: 0.000219 AC: 18 AN: 82250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.000371 AC: 2 AN: 5390

European-Non Finnish (NFE) AF: 0.0000565 AC: 53 AN: 937418

Other (OTH) AF: 0.0000742 AC: 4 AN: 53902

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Congenital myasthenic syndrome 12 (2)
-	-	1	GFPT1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.37
DANN	Benign	0.58
PhyloP100		-0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00031
dbscSNV1_RF	Benign	0.030
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: rs753072061; hg19: chr2-69573141;