chr2-69369996-G-A

Variant names:

• chr2-69369996-G-A
• rs200631666
• NM_001244710.2:c.223+5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001244710.2(GFPT1):​c.223+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,474,526 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (7 hom.)
• Consequence: GFPT1 NM_001244710.2 splice_region, intron
• Scores: Splicing: ADA: 0.00009910
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.209
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 2-69369996-G-A is Benign according to our data. Variant chr2-69369996-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 336881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000394 (60/152232) while in subpopulation SAS AF = 0.00415 (20/4822). AF 95% confidence interval is 0.00275. There are 1 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.223+5C>T		splice_region intron	N/A	NP_001231639.1	Q06210-1
	GFPT1	NM_002056.4		c.223+5C>T		splice_region intron	N/A	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.223+5C>T		splice_region intron	N/A	ENSP00000349860.4	Q06210-1
	GFPT1	ENST00000361060.5	TSL:1	c.223+5C>T		splice_region intron	N/A	ENSP00000354347.4	Q06210-2
	GFPT1	ENST00000955842.1		c.223+5C>T		splice_region intron	N/A	ENSP00000625901.1

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152114 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00101 AC: 255 AN: 251364 AF XY: 0.00131

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000369

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000582 AC: 769 AN: 1322294 Hom.: 7 Cov.: 22 AF XY: 0.000770 AC XY: 512 AN XY: 665164

African (AFR) AF: 0.0000969 AC: 3 AN: 30958

American (AMR) AF: 0.000247 AC: 11 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.000158 AC: 4 AN: 25268

East Asian (EAS) AF: 0.000333 AC: 13 AN: 39004

South Asian (SAS) AF: 0.00575 AC: 480 AN: 83458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00364 AC: 20 AN: 5496

European-Non Finnish (NFE) AF: 0.000205 AC: 202 AN: 984562

Other (OTH) AF: 0.000647 AC: 36 AN: 55678

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152232 Hom.: 1 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74440

African (AFR) AF: 0.0000963 AC: 4 AN: 41542

American (AMR) AF: 0.000131 AC: 2 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000292 Hom.: 0

Bravo AF: 0.000272

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	14
DANN	Benign	0.52
PhyloP100		-0.21
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000099
SpliceAI score (max)		0.060		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: rs200631666; hg19: chr2-69597128;