Genetic Variant GART:p.Val421Ile (chr21-33524806-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000819.5(GART):c.1261G>A(p.Val421Ile) variant causes a missense change. The variant allele was found at a frequency of 0.785 in 1,614,086 control chromosomes in the GnomAD database, including 500,004 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.82 ( 51808 hom., cov: 33)

Exomes 𝑓: 0.78 ( 448196 hom. )

Consequence

GART
NM_000819.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.77

Publications

36 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.5641482E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GART	NM_000819.5 link	c.1261G>A	p.Val421Ile	missense_variant	Exon 11 of 22	ENST00000381815.9	NP_000810.1	P22102-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GART	ENST00000381815.9 link	c.1261G>A	p.Val421Ile	missense_variant	Exon 11 of 22	1	NM_000819.5	ENSP00000371236.4		P22102-1

Frequencies

GnomAD3 genomes

AF:

0.822

AC:

125072

AN:

152138

Hom.:

51754

Cov.:

show subpopulations

Gnomad AFR

AF:

0.900

Gnomad AMI

AF:

0.714

Gnomad AMR

AF:

0.859

Gnomad ASJ

AF:

0.710

Gnomad EAS

AF:

0.983

Gnomad SAS

AF:

0.785

Gnomad FIN

AF:

0.830

Gnomad MID

AF:

0.696

Gnomad NFE

AF:

0.764

Gnomad OTH

AF:

0.797

GnomAD2 exomes

AF:

0.812

AC:

204156

AN:

251440

AF XY:

0.803

show subpopulations

Gnomad AFR exome

AF:

0.904

Gnomad AMR exome

AF:

0.896

Gnomad ASJ exome

AF:

0.708

Gnomad EAS exome

AF:

0.993

Gnomad FIN exome

AF:

0.831

Gnomad NFE exome

AF:

0.761

Gnomad OTH exome

AF:

0.790

GnomAD4 exome

AF:

0.781

AC:

1142198

AN:

1461828

Hom.:

448196

Cov.:

AF XY:

0.779

AC XY:

566721

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.905

AC:

30297

AN:

33478

American (AMR)

AF:

0.890

AC:

39813

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.715

AC:

18685

AN:

26136

East Asian (EAS)

AF:

0.976

AC:

38767

AN:

39700

South Asian (SAS)

AF:

0.772

AC:

66565

AN:

86256

European-Finnish (FIN)

AF:

0.822

AC:

43927

AN:

53416

Middle Eastern (MID)

AF:

0.722

AC:

4167

AN:

5768

European-Non Finnish (NFE)

AF:

0.766

AC:

852089

AN:

1111954

Other (OTH)

AF:

0.793

AC:

47888

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

13916

27832

41749

55665

69581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20536

41072

61608

82144

102680

<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:

0.822

AC:

125185

AN:

152258

Hom.:

51808

Cov.:

AF XY:

0.827

AC XY:

61586

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.900

AC:

37426

AN:

41566

American (AMR)

AF:

0.859

AC:

13147

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.710

AC:

2464

AN:

3472

East Asian (EAS)

AF:

0.983

AC:

5094

AN:

5182

South Asian (SAS)

AF:

0.783

AC:

3784

AN:

4830

European-Finnish (FIN)

AF:

0.830

AC:

8793

AN:

10594

Middle Eastern (MID)

AF:

0.694

AC:

204

AN:

294

European-Non Finnish (NFE)

AF:

0.764

AC:

51935

AN:

67996

Other (OTH)

AF:

0.799

AC:

1688

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1143

2286

3429

4572

5715

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

882

1764

2646

3528

4410

<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:

0.784

Hom.:

122783

Bravo

AF:

0.832

TwinsUK

AF:

0.772

AC:

2861

ALSPAC

AF:

0.761

AC:

2933

ESP6500AA

AF:

0.902

AC:

3973

ESP6500EA

AF:

0.761

AC:

6541

ExAC

AF:

0.808

AC:

98085

Asia WGS

AF:

0.911

AC:

3169

AN:

3478

EpiCase

AF:

0.751

EpiControl

AF:

0.749

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.049

T;T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.64

.;.;T;T

MetaRNN

Benign

0.0000026

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-3.8

N;N;N;N

PhyloP100

5.8

PrimateAI

Benign

0.48

PROVEAN

Benign

0.92

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.054

MPC

0.081

ClinPred

0.0068

GERP RS

6.0

Varity_R

0.036

gMVP

0.79

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over