Genetic Variant GART:p.Glu177Gln (chr21-33531557-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000819.5(GART):c.529G>C(p.Glu177Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000145 in 1,588,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

GART
NM_000819.5 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.15

Publications

0 publications found

Variant links:

Genes affected

GART (HGNC:4163): (phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase) The protein encoded by this gene is a trifunctional polypeptide. It has phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, phosphoribosylaminoimidazole synthetase activity which is required for de novo purine biosynthesis. This enzyme is highly conserved in vertebrates. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

GART links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000819.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GART	NM_000819.5	MANE Select	c.529G>C	p.Glu177Gln	missense splice_region	Exon 6 of 22	NP_000810.1
GART	NM_001136005.1		c.529G>C	p.Glu177Gln	missense splice_region	Exon 6 of 22	NP_001129477.1
GART	NM_001136006.1		c.529G>C	p.Glu177Gln	missense splice_region	Exon 6 of 22	NP_001129478.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GART	ENST00000381815.9	TSL:1 MANE Select	c.529G>C	p.Glu177Gln	missense splice_region	Exon 6 of 22	ENSP00000371236.4
GART	ENST00000381831.7	TSL:1	c.529G>C	p.Glu177Gln	missense splice_region	Exon 6 of 22	ENSP00000371253.3
GART	ENST00000381839.7	TSL:1	c.529G>C	p.Glu177Gln	missense splice_region	Exon 6 of 22	ENSP00000371261.3

Frequencies

GnomAD3 genomes

AF:

0.0000332

AC:

AN:

150660

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000194

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000222

AC:

AN:

225434

AF XY:

0.0000326

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000156

Gnomad NFE exome

AF:

0.0000188

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000125

AC:

AN:

1438156

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

715128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31720

American (AMR)

AF:

0.00

AC:

AN:

38864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25288

East Asian (EAS)

AF:

0.00

AC:

AN:

39590

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80836

European-Finnish (FIN)

AF:

0.000136

AC:

AN:

51290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

0.00000724

AC:

AN:

1105514

Other (OTH)

AF:

0.0000337

AC:

AN:

59410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000332

AC:

AN:

150660

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73484

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40694

American (AMR)

AF:

0.00

AC:

AN:

15076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.000194

AC:

AN:

10318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67898

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

0.060

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.029

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

4.1

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.96

REVEL

Benign

0.13

Sift

Benign

0.084

Sift4G

Benign

0.12

Polyphen

0.0030

Vest4

0.12

MutPred

0.43

Loss of disorder (P = 0.1411)

MVP

0.73

MPC

0.11

ClinPred

0.15

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.34

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.72

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.72

Position offset: -3

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over