Genetic Variant GFPT1:c.686-2A>C (chr2-69354314-T-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

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

Publications

0 publications found

Variant links:

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

GFPT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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	Effect	Exon rank	MANE	Protein	UniProt
GFPT1	NM_001244710.2 link	c.686-2A>C	splice_acceptor_variant, intron_variant	Intron 8 of 19	ENST00000357308.9	NP_001231639.1	Q06210-1
GFPT1	NM_002056.4 link	c.685+175A>C	intron_variant	Intron 8 of 18		NP_002047.2	Q06210-2
GFPT1	XM_017003801.2 link	c.761-2A>C	splice_acceptor_variant, intron_variant	Intron 8 of 19		XP_016859290.1
GFPT1	XM_017003802.3 link	c.760+175A>C	intron_variant	Intron 8 of 18		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GFPT1	ENST00000357308.9 link	c.686-2A>C	splice_acceptor_variant, intron_variant	Intron 8 of 19	5	NM_001244710.2	ENSP00000349860.4	Q06210-1
GFPT1	ENST00000361060.5 link	c.685+175A>C	intron_variant	Intron 8 of 18	1		ENSP00000354347.4	Q06210-2
GFPT1	ENST00000674507.1 link	c.685+175A>C	intron_variant	Intron 8 of 17			ENSP00000501332.1	A0A6I8PTT9
GFPT1	ENST00000674438.1 link	c.469+175A>C	intron_variant	Intron 6 of 16			ENSP00000501469.1	A0A6I8PRN4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1437246

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714752

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33296

American (AMR)

AF:

0.00

AC:

AN:

43662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25850

East Asian (EAS)

AF:

0.00

AC:

AN:

39514

South Asian (SAS)

AF:

0.00

AC:

AN:

84888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1105454

Other (OTH)

AF:

0.00

AC:

AN:

59980

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Uncertain

0.95

PhyloP100

4.9

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=2/98

disease causing

(source)

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

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2-69354314-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over