NM_001244710.2:c.549T>C

Variant names:

• chr2-69356552-A-G
• rs144566433
• NM_001244710.2:c.549T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001244710.2(GFPT1):​c.549T>C​(p.Gly183Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00043 in 1,612,300 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (3 hom.)
• Consequence: GFPT1 NM_001244710.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.04
• Publications: 1 publications found

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), Ambry Genetics, ClinGen, Illumina
• congenital myasthenic syndromes with glycosylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-69356552-A-G is Benign according to our data. Variant chr2-69356552-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00227 (345/152254) while in subpopulation AFR AF = 0.00775 (322/41562). AF 95% confidence interval is 0.00705. There are 1 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244710.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFPT1	NM_001244710.2	MANE Select	c.549T>C	p.Gly183Gly	synonymous	Exon 7 of 20	NP_001231639.1	Q06210-1
	GFPT1	NM_002056.4		c.549T>C	p.Gly183Gly	synonymous	Exon 7 of 19	NP_002047.2	Q06210-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFPT1	ENST00000357308.9	TSL:5 MANE Select	c.549T>C	p.Gly183Gly	synonymous	Exon 7 of 20	ENSP00000349860.4	Q06210-1
	GFPT1	ENST00000361060.5	TSL:1	c.549T>C	p.Gly183Gly	synonymous	Exon 7 of 19	ENSP00000354347.4	Q06210-2
	GFPT1	ENST00000955842.1		c.597T>C	p.Gly199Gly	synonymous	Exon 8 of 21	ENSP00000625901.1

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152134 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

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: 0.00

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000493 AC: 124 AN: 251330 AF XY: 0.000383

Gnomad AFR exome AF: 0.00683

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000239 AC: 349 AN: 1460046 Hom.: 3 Cov.: 29 AF XY: 0.000206 AC XY: 150 AN XY: 726510

African (AFR) AF: 0.00828 AC: 277 AN: 33434

American (AMR) AF: 0.000559 AC: 25 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1110426

Other (OTH) AF: 0.000530 AC: 32 AN: 60328

GnomAD4 genome AF: 0.00227 AC: 345 AN: 152254 Hom.: 1 Cov.: 33 AF XY: 0.00203 AC XY: 151 AN XY: 74448

African (AFR) AF: 0.00775 AC: 322 AN: 41562

American (AMR) AF: 0.00137 AC: 21 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.00262

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Congenital myasthenic syndrome 12 (1)
-	-	1	GFPT1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.6
DANN	Benign	0.88
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs144566433; hg19: chr2-69583684;