21-33524806-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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	c.1261G>A	p.Val421Ile	missense_variant	Exon 11 of 22	ENST00000381815.9	NP_000810.1

Ensembl

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

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

GnomAD3 exomes AF: 0.812 AC: 204156 AN: 251440 Hom.: 83749 AF XY: 0.803 AC XY: 109108 AN XY: 135894

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 SAS exome AF: 0.774

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

Gnomad4 AFR exome AF: 0.905

Gnomad4 AMR exome AF: 0.890

Gnomad4 ASJ exome AF: 0.715

Gnomad4 EAS exome AF: 0.976

Gnomad4 SAS exome AF: 0.772

Gnomad4 FIN exome AF: 0.822

Gnomad4 NFE exome AF: 0.766

Gnomad4 OTH exome AF: 0.793

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

Gnomad4 AFR AF: 0.900

Gnomad4 AMR AF: 0.859

Gnomad4 ASJ AF: 0.710

Gnomad4 EAS AF: 0.983

Gnomad4 SAS AF: 0.783

Gnomad4 FIN AF: 0.830

Gnomad4 NFE AF: 0.764

Gnomad4 OTH AF: 0.799

Alfa AF: 0.779 Hom.: 83723

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	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
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	N
LIST_S2	Benign	0.64	.;.;T;T
MetaRNN	Benign	0.0000026	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.8	N;N;N;N
PrimateAI	Benign	0.48	T
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	T
GERP RS		6.0
Varity_R		0.036
gMVP		0.79

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

LitVar

Other links and lift over

dbSNP: rs8788; hg19: chr21-34897113;