16-88809715-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000485.3(APRT):c.526C>T(p.Leu176Phe) variant causes a missense change. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: APRT NM_000485.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.63

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a strand (size 6) in uniprot entity APT_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000485.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 16-88809715-G-A is Pathogenic according to our data. Variant chr16-88809715-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 988022.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-88809715-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APRT	NM_000485.3	c.526C>T	p.Leu176Phe	missense_variant	5/5	ENST00000378364.8
APRT	NM_001030018.2	c.401-9C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APRT	ENST00000378364.8	c.526C>T	p.Leu176Phe	missense_variant	5/5	1	NM_000485.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Adenine phosphoribosyltransferase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

APRT Deficiency Research Program of the Rare Kidney Stone Consortium, Landspitali, National University Hospital of Iceland

Sep 01, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0050	D;T
Sift4G	Benign	0.19	T;D
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.82		Gain of catalytic residue at L176 (P = 0.1309);.;
MVP		0.94
MPC		0.63
ClinPred		0.98	D
GERP RS		3.2
Varity_R		0.62
gMVP		0.52

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: rs1909033869; hg19: chr16-88876123;