NM_000485.3:c.294G>C

Variant names:

• chr16-88810450-C-G
• rs104894507
• NM_000485.3:c.294G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000485.3(APRT):​c.294G>C​(p.Trp98Cys) 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. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. W98L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: APRT NM_000485.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.85
• Publications: 0 publications found

Genes affected

APRT (HGNC:626): (adenine phosphoribosyltransferase) Adenine phosphoribosyltransferase belongs to the purine/pyrimidine phosphoribosyltransferase family. A conserved feature of this gene is the distribution of CpG dinucleotides. This enzyme catalyzes the formation of AMP and inorganic pyrophosphate from adenine and 5-phosphoribosyl-1-pyrophosphate (PRPP). It also produces adenine as a by-product of the polyamine biosynthesis pathway. A homozygous deficiency in this enzyme causes 2,8-dihydroxyadenine urolithiasis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

APRT Gene-Disease associations (from GenCC):

• adenine phosphoribosyltransferase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 23 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: -0.23784 (below the threshold of 3.09). Trascript score misZ: -1.8306 (below the threshold of 3.09). GenCC associations: The gene is linked to adenine phosphoribosyltransferase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.091836154).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000485.3. 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
	APRT	NM_000485.3	MANE Select	c.294G>C	p.Trp98Cys	missense	Exon 3 of 5	NP_000476.1	P07741-1
	APRT	NM_001030018.2		c.294G>C	p.Trp98Cys	missense	Exon 3 of 5	NP_001025189.1	P07741-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APRT	ENST00000378364.8	TSL:1 MANE Select	c.294G>C	p.Trp98Cys	missense	Exon 3 of 5	ENSP00000367615.3	P07741-1
	APRT	ENST00000912471.1		c.540G>C	p.Trp180Cys	missense	Exon 3 of 5	ENSP00000582530.1
	APRT	ENST00000880214.1		c.387G>C	p.Trp129Cys	missense	Exon 3 of 5	ENSP00000550273.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	0.0040
DANN	Benign	0.71
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.092	T
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-4.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.59	N
REVEL	Uncertain	0.43
Sift	Benign	0.031	D
Sift4G	Benign	0.083	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.46		Gain of catalytic residue at S100 (P = 0.0541)
MVP		0.57
MPC		0.22
ClinPred		0.078	T
GERP RS		-9.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.66

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: rs104894507; hg19: chr16-88876858;