21-33506044-T-C

Position:

• chr21-33506044-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000819.5(GART):​c.2513A>G​(p.Asp838Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GART NM_000819.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.93

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17807233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GART	NM_000819.5	c.2513A>G	p.Asp838Gly	missense_variant	19/22	ENST00000381815.9	NP_000810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GART	ENST00000381815.9	c.2513A>G	p.Asp838Gly	missense_variant	19/22	1	NM_000819.5	ENSP00000371236	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.2513A>G (p.D838G) alteration is located in exon 19 (coding exon 18) of the GART gene. This alteration results from a A to G substitution at nucleotide position 2513, causing the aspartic acid (D) at amino acid position 838 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.61	D
LIST_S2	Pathogenic	0.98	.;.;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.13	N;N;N
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.0	N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.011	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.015	B;B;B
Vest4		0.42
MutPred		0.59		Loss of stability (P = 0.0354);Loss of stability (P = 0.0354);Loss of stability (P = 0.0354);
MVP		0.62
MPC		0.15
ClinPred		0.34	T
GERP RS		2.5
Varity_R		0.27
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-34878351;