rs112682152

chr2-69359261-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001244710.2(GFPT1):c.408+7A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,502,278 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (32 hom.)
• Consequence: GFPT1 NM_001244710.2 splice_region, intron
• Scores: Splicing: ADA: 0.0003589
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.491

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-69359261-T-A is Benign according to our data. Variant chr2-69359261-T-A is described in ClinVar as [Benign]. Clinvar id is 257668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-69359261-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1737/152288) while in subpopulation AFR AF= 0.0395 (1641/41560). AF 95% confidence interval is 0.0379. There are 30 homozygotes in gnomad4. There are 799 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFPT1	NM_001244710.2	c.408+7A>T		splice_region_variant, intron_variant		ENST00000357308.9
GFPT1	NM_002056.4	c.408+7A>T		splice_region_variant, intron_variant
GFPT1	XM_017003801.2	c.483+7A>T		splice_region_variant, intron_variant
GFPT1	XM_017003802.3	c.483+7A>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFPT1	ENST00000357308.9	c.408+7A>T		splice_region_variant, intron_variant		5	NM_001244710.2
GFPT1	ENST00000361060.5	c.408+7A>T		splice_region_variant, intron_variant		1		P1
GFPT1	ENST00000674438.1	c.192+7A>T		splice_region_variant, intron_variant
GFPT1	ENST00000674507.1	c.408+7A>T		splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1731 AN: 152170 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0395

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00309 AC: 775 AN: 251144 Hom.: 13 AF XY: 0.00224 AC XY: 304 AN XY: 135738

Gnomad AFR exome AF: 0.0430

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00114 AC: 1543 AN: 1349990 Hom.: 32 Cov.: 21 AF XY: 0.000949 AC XY: 643 AN XY: 677872

Gnomad4 AFR exome AF: 0.0407

Gnomad4 AMR exome AF: 0.00175

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000107

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000237

Gnomad4 OTH exome AF: 0.00256

GnomAD4 genome AF: 0.0114 AC: 1737 AN: 152288 Hom.: 30 Cov.: 32 AF XY: 0.0107 AC XY: 799 AN XY: 74464

Gnomad4 AFR AF: 0.0395

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00366 Hom.: 6

Bravo AF: 0.0135

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 07, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	9.0
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00036
dbscSNV1_RF	Benign	0.014
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: rs112682152; hg19: chr2-69586393;