21-33524806-C-T

Variant names:

• chr21-33524806-C-T
• rs8788
• NM_000819.5:c.1261G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.77
• Publications: 36 publications found

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]

ACMG classification

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GART	NM_000819.5	MANE Select	c.1261G>A	p.Val421Ile	missense	Exon 11 of 22	NP_000810.1	P22102-1
	GART	NM_001136005.1		c.1261G>A	p.Val421Ile	missense	Exon 11 of 22	NP_001129477.1	P22102-1
	GART	NM_001136006.1		c.1261G>A	p.Val421Ile	missense	Exon 11 of 22	NP_001129478.1	P22102-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GART	ENST00000381815.9	TSL:1 MANE Select	c.1261G>A	p.Val421Ile	missense	Exon 11 of 22	ENSP00000371236.4	P22102-1
	GART	ENST00000381831.7	TSL:1	c.1261G>A	p.Val421Ile	missense	Exon 11 of 22	ENSP00000371253.3	P22102-1
	GART	ENST00000381839.7	TSL:1	c.1261G>A	p.Val421Ile	missense	Exon 11 of 22	ENSP00000371261.3	P22102-1

Frequencies

GnomAD3 genomes AF: 0.822 AC: 125072 AN: 152138 Hom.: 51754 Cov.: 33

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

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.: 63 AF XY: 0.779 AC XY: 566721 AN XY: 727216

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

GnomAD4 genome AF: 0.822 AC: 125185 AN: 152258 Hom.: 51808 Cov.: 33 AF XY: 0.827 AC XY: 61586 AN XY: 74458

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.14
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0000026	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.8	N
PhyloP100		5.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.054
MPC		0.081
ClinPred		0.0068	T
GERP RS		6.0
Varity_R		0.036
gMVP		0.79
Mutation Taster		=79/21	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: rs8788; hg19: chr21-34897113; COSMIC: COSV107456620; COSMIC: COSV107456620;