Genetic Variant GMPS:c.209+5A>G (chr3-155893704-A-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003875.3(GMPS):c.209+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 0.00874 in 1,538,782 control chromosomes in the GnomAD database, including 71 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0089 ( 63 hom. )

Consequence

GMPS
NM_003875.3 splice_region, intron

Scores

Splicing: ADA: 0.00004479

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.229

Publications

3 publications found

Variant links:

Genes affected

GMPS (HGNC:4378): (guanine monophosphate synthase) In the de novo synthesis of purine nucleotides, IMP is the branch point metabolite at which point the pathway diverges to the synthesis of either guanine or adenine nucleotides. In the guanine nucleotide pathway, there are 2 enzymes involved in converting IMP to GMP, namely IMP dehydrogenase (IMPD1), which catalyzes the oxidation of IMP to XMP, and GMP synthetase, which catalyzes the amination of XMP to GMP. [provided by RefSeq, Jul 2008]

GMPS links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 3-155893704-A-G is Benign according to our data. Variant chr3-155893704-A-G is described in ClinVar as Benign. ClinVar VariationId is 777587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1051 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003875.3. 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
	GMPS	NM_003875.3	MANE Select	c.209+5A>G		splice_region intron	N/A	NP_003866.1	A0A140VJK6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GMPS	ENST00000496455.7	TSL:1 MANE Select	c.209+5A>G	splice_region intron	N/A	ENSP00000419851.1	P49915-1
GMPS	ENST00000928984.1		c.209+5A>G	splice_region intron	N/A	ENSP00000599043.1
GMPS	ENST00000967990.1		c.209+5A>G	splice_region intron	N/A	ENSP00000638049.1

Frequencies

GnomAD3 genomes

AF:

0.00689

AC:

1049

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00668

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0108

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00609

AC:

1381

AN:

226586

AF XY:

0.00601

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00445

Gnomad ASJ exome

AF:

0.00112

Gnomad EAS exome

AF:

0.0000602

Gnomad FIN exome

AF:

0.00529

Gnomad NFE exome

AF:

0.00979

Gnomad OTH exome

AF:

0.00661

GnomAD4 exome

AF:

0.00894

AC:

12399

AN:

1386476

Hom.:

Cov.:

AF XY:

0.00878

AC XY:

6078

AN XY:

692230

show subpopulations

African (AFR)

AF:

0.000987

AC:

AN:

31396

American (AMR)

AF:

0.00495

AC:

197

AN:

39780

Ashkenazi Jewish (ASJ)

AF:

0.00169

AC:

AN:

24916

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38806

South Asian (SAS)

AF:

0.00203

AC:

165

AN:

81392

European-Finnish (FIN)

AF:

0.00515

AC:

273

AN:

53038

Middle Eastern (MID)

AF:

0.00633

AC:

AN:

5526

European-Non Finnish (NFE)

AF:

0.0107

AC:

11245

AN:

1053936

Other (OTH)

AF:

0.00711

AC:

410

AN:

57686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

523

1045

1568

2090

2613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

422

844

1266

1688

2110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00690

AC:

1051

AN:

152306

Hom.:

Cov.:

AF XY:

0.00677

AC XY:

504

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00204

AC:

AN:

41574

American (AMR)

AF:

0.00758

AC:

116

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00668

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0109

AC:

738

AN:

68018

Other (OTH)

AF:

0.0118

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00850

Hom.:

Bravo

AF:

0.00678

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

6.9

(source)

DANN

Benign

0.66

PhyloP100

0.23

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000045

dbscSNV1_RF

Benign

0.012

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over