rs2230300

Positions:

• chr2-69370077-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001244710.2(GFPT1):​c.147T>C​(p.Asp49Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,610,460 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (35 hom., cov: 32)
  • Exomes 𝑓: 0.020 (396 hom.)
• Consequence: GFPT1 NM_001244710.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.441

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-69370077-A-G is Benign according to our data. Variant chr2-69370077-A-G is described in ClinVar as [Benign]. Clinvar id is 129152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-69370077-A-G is described in Lovd as [Likely_benign]. Variant chr2-69370077-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.441 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0162 (2474/152296) while in subpopulation NFE AF= 0.0248 (1690/68024). AF 95% confidence interval is 0.0239. There are 35 homozygotes in gnomad4. There are 1172 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFPT1	NM_001244710.2	c.147T>C	p.Asp49Asp	synonymous_variant	3/20	ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4	c.147T>C	p.Asp49Asp	synonymous_variant	3/19		NP_002047.2
GFPT1	XM_017003801.2	c.222T>C	p.Asp74Asp	synonymous_variant	3/20		XP_016859290.1
GFPT1	XM_017003802.3	c.222T>C	p.Asp74Asp	synonymous_variant	3/19		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9	c.147T>C	p.Asp49Asp	synonymous_variant	3/20	5	NM_001244710.2	ENSP00000349860.4

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2471 AN: 152178 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0162 AC: 4083 AN: 251410 Hom.: 49 AF XY: 0.0167 AC XY: 2270 AN XY: 135878

Gnomad AFR exome AF: 0.00425

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0201

GnomAD4 exome AF: 0.0205 AC: 29836 AN: 1458164 Hom.: 396 Cov.: 29 AF XY: 0.0202 AC XY: 14643 AN XY: 725622

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00337

Gnomad4 FIN exome AF: 0.0226

Gnomad4 NFE exome AF: 0.0239

Gnomad4 OTH exome AF: 0.0173

GnomAD4 genome AF: 0.0162 AC: 2474 AN: 152296 Hom.: 35 Cov.: 32 AF XY: 0.0157 AC XY: 1172 AN XY: 74468

Gnomad4 AFR AF: 0.00450

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0263

Gnomad4 NFE AF: 0.0248

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0197 Hom.: 74

Bravo AF: 0.0154

Asia WGS AF: 0.00318 AC: 12 AN: 3478

EpiCase AF: 0.0231

EpiControl AF: 0.0232

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 24, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Congenital myasthenic syndrome 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.8
DANN	Benign	0.63
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2230300; hg19: chr2-69597209;