chr21-33517404-A-C

Position:

• chr21-33517404-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000819.5(GART):​c.1907T>G​(p.Leu636Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GART NM_000819.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.40

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 21-33517404-A-C is Pathogenic according to our data. Variant chr21-33517404-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 916559.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GART	NM_000819.5	c.1907T>G	p.Leu636Arg	missense_variant	15/22	ENST00000381815.9	NP_000810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GART	ENST00000381815.9	c.1907T>G	p.Leu636Arg	missense_variant	15/22	1	NM_000819.5	ENSP00000371236	P1
GART	ENST00000381831.7	c.1907T>G	p.Leu636Arg	missense_variant	15/22	1		ENSP00000371253	P1
GART	ENST00000381839.7	c.1907T>G	p.Leu636Arg	missense_variant	15/22	1		ENSP00000371261	P1
GART	ENST00000424203.5	c.*990T>G		3_prime_UTR_variant, NMD_transcript_variant	15/22	1		ENSP00000390003

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Tracheoesophageal fistula Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Shen Lab, Columbia University Medical Center

Jul 01, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	.;.;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Pathogenic	3.5	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.023	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.91	P;P;P
Vest4		0.63
MutPred		0.73		Gain of solvent accessibility (P = 0.0039);Gain of solvent accessibility (P = 0.0039);Gain of solvent accessibility (P = 0.0039);
MVP		0.57
MPC		0.59
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.91

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: rs2084898135; hg19: chr21-34889711;