chr2-69329679-T-C

Position:

chr2-69329679-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001244710.2(GFPT1):c.1597+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000575 in 1,583,600 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000054 ( 1 hom. )

Consequence

GFPT1
NM_001244710.2 splice_region, intron

Scores

Splicing: ADA: 0.0006693

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.181

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=-0.74).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
GFPT1	NM_001244710.2 linkuse as main transcript	c.1597+5A>G	splice_region_variant, intron_variant	ENST00000357308.9	NP_001231639.1	Q06210-1
GFPT1	NM_002056.4 linkuse as main transcript	c.1543+5A>G	splice_region_variant, intron_variant		NP_002047.2	Q06210-2
GFPT1	XM_017003801.2 linkuse as main transcript	c.1672+5A>G	splice_region_variant, intron_variant		XP_016859290.1
GFPT1	XM_017003802.3 linkuse as main transcript	c.1618+5A>G	splice_region_variant, intron_variant		XP_016859291.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
GFPT1	ENST00000357308.9 linkuse as main transcript	c.1597+5A>G	splice_region_variant, intron_variant	5	NM_001244710.2	ENSP00000349860.4	Q06210-1
GFPT1	ENST00000361060.5 linkuse as main transcript	c.1543+5A>G	splice_region_variant, intron_variant	1		ENSP00000354347.4	Q06210-2
GFPT1	ENST00000674507.1 linkuse as main transcript	c.1543+5A>G	splice_region_variant, intron_variant			ENSP00000501332.1	A0A6I8PTT9
GFPT1	ENST00000674438.1 linkuse as main transcript	c.1327+5A>G	splice_region_variant, intron_variant			ENSP00000501469.1	A0A6I8PRN4

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251426

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000538

AC:

AN:

1431284

Hom.:

Cov.:

AF XY:

0.0000588

AC XY:

AN XY:

714048

show subpopulations

Gnomad4 AFR exome

AF:

0.000213

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000642

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.0000337

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000464

Hom.:

Bravo

AF:

0.000106

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 12

Uncertain:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 18, 2023	This sequence change falls in intron 16 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 present in population databases (rs373420002, gnomAD 0.06%). 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: 336876). 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 is not likely to affect RNA splicing. 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00067

dbscSNV1_RF

Benign

0.084

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over