NM_000485.3:c.448G>A

Variant names:

• chr16-88809793-C-T
• rs281860266
• NM_000485.3:c.448G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000485.3(APRT):​c.448G>A​(p.Val150Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V150F) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
• Consequence: APRT NM_000485.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.270

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Adenine phosphoribosyltransferase (size 178) in uniprot entity APT_HUMAN there are 22 pathogenic changes around while only 1 benign (96%) in NM_000485.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-88809793-C-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2854799).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APRT	NM_000485.3	c.448G>A	p.Val150Ile	missense_variant	Exon 5 of 5	ENST00000378364.8	NP_000476.1
APRT	NM_001030018.2	c.401-87G>A		intron_variant	Intron 4 of 4		NP_001025189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APRT	ENST00000378364.8	c.448G>A	p.Val150Ile	missense_variant	Exon 5 of 5	1	NM_000485.3	ENSP00000367615.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.86	D;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	0.93	L;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.44	N;N
REVEL	Uncertain	0.41
Sift	Benign	0.37	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.21	B;.
Vest4		0.094
MutPred		0.64		Loss of phosphorylation at S155 (P = 0.2828);.;
MVP		0.75
MPC		0.14
ClinPred		0.34	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.29

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: rs281860266; hg19: chr16-88876201;