2-69354314-T-G

Variant names:

• chr2-69354314-T-G
• NM_001244710.2:c.686-2A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001244710.2(GFPT1):​c.686-2A>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000696 in 1,437,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: GFPT1 NM_001244710.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9434
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.94

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.025714286 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.7, offset of 4, new splice context is: tgttgtgtatccttcgctAGgac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFPT1	NM_001244710.2	c.686-2A>C		splice_acceptor_variant, intron_variant	Intron 8 of 19	ENST00000357308.9	NP_001231639.1
GFPT1	NM_002056.4	c.685+175A>C		intron_variant	Intron 8 of 18		NP_002047.2
GFPT1	XM_017003801.2	c.761-2A>C		splice_acceptor_variant, intron_variant	Intron 8 of 19		XP_016859290.1
GFPT1	XM_017003802.3	c.760+175A>C		intron_variant	Intron 8 of 18		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFPT1	ENST00000357308.9	c.686-2A>C		splice_acceptor_variant, intron_variant	Intron 8 of 19	5	NM_001244710.2	ENSP00000349860.4
GFPT1	ENST00000361060.5	c.685+175A>C		intron_variant	Intron 8 of 18	1		ENSP00000354347.4
GFPT1	ENST00000674507.1	c.685+175A>C		intron_variant	Intron 8 of 17			ENSP00000501332.1
GFPT1	ENST00000674438.1	c.469+175A>C		intron_variant	Intron 6 of 16			ENSP00000501469.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437246 Hom.: 0 Cov.: 28 AF XY: 0.00000140 AC XY: 1 AN XY: 714752

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -6

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-69581446;