rs190072721

chr2-69328282-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4_Strong BP6

The NM_001244710.2(GFPT1):c.1882G>A(p.Val628Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000696 in 1,613,704 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (3 hom.)
• Consequence: GFPT1 NM_001244710.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.49

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 -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GFPT1
• BP4: Computational evidence support a benign effect (MetaRNN=0.013113409).
• BP6: Variant 2-69328282-C-T is Benign according to our data. Variant chr2-69328282-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435319.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFPT1	NM_001244710.2	c.1882G>A	p.Val628Ile	missense_variant	18/20	ENST00000357308.9
GFPT1	NM_002056.4	c.1828G>A	p.Val610Ile	missense_variant	17/19
GFPT1	XM_017003801.2	c.1957G>A	p.Val653Ile	missense_variant	18/20
GFPT1	XM_017003802.3	c.1903G>A	p.Val635Ile	missense_variant	17/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFPT1	ENST00000357308.9	c.1882G>A	p.Val628Ile	missense_variant	18/20	5	NM_001244710.2
GFPT1	ENST00000361060.5	c.1828G>A	p.Val610Ile	missense_variant	17/19	1		P1
GFPT1	ENST00000674438.1	c.1612G>A	p.Val538Ile	missense_variant	15/17
GFPT1	ENST00000674507.1	c.1671+1015G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.000947 AC: 144 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000904 AC: 227 AN: 251170 Hom.: 0 AF XY: 0.000913 AC XY: 124 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.00346

Gnomad NFE exome AF: 0.000899

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000670 AC: 979 AN: 1461462 Hom.: 3 Cov.: 31 AF XY: 0.000696 AC XY: 506 AN XY: 727056

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000939

Gnomad4 FIN exome AF: 0.00395

Gnomad4 NFE exome AF: 0.000556

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000946 AC: 144 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74444

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.00135

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000989 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000832 AC: 101

EpiCase AF: 0.000981

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome 12 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	15
Dann	Benign	0.88
DEOGEN2	Uncertain	0.50	T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.56	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.028
Sift	Benign	0.55	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0	.;B
Vest4		0.19
MVP		0.44
MPC		0.94
ClinPred		0.022	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.043
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs190072721; hg19: chr2-69555414;