rs1286081479

Positions:

• chr2-69354571-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001244710.2(GFPT1):​c.606-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000439 in 1,593,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: GFPT1 NM_001244710.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001438
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFPT1	NM_001244710.2	c.606-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4	c.606-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_002047.2
GFPT1	XM_017003801.2	c.681-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_016859290.1
GFPT1	XM_017003802.3	c.681-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9	c.606-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001244710.2	ENSP00000349860
GFPT1	ENST00000361060.5	c.606-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000354347	P1
GFPT1	ENST00000674438.1	c.390-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000501469
GFPT1	ENST00000674507.1	c.606-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000501332

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1440956 Hom.: 0 Cov.: 26 AF XY: 0.00000278 AC XY: 2 AN XY: 718318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000366

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2022

This sequence change falls in intron 7 of the GFPT1 gene. It does not directly change the encoded amino acid sequence of the GFPT1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GFPT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 473135). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.3
DANN	Benign	0.68
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1286081479; hg19: chr2-69581703;