rs28999113

chr16-88809834-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PM1 PM2 PP3_Strong PP5 BS1_Supporting

The NM_000485.3(APRT):c.407T>C(p.Met136Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000363 in 1,459,600 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M136V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000036 (1 hom.)
• Consequence: APRT NM_000485.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 6.78

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 8 ACMG points.

• PM1: In a helix (size 11) in uniprot entity APT_HUMAN there are 4 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, 0.989
• PP5: Variant 16-88809834-A-G is Pathogenic according to our data. Variant chr16-88809834-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 18296.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-88809834-A-G is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000363 (53/1459600) while in subpopulation EAS AF= 0.00116 (46/39694). AF 95% confidence interval is 0.000892. There are 1 homozygotes in gnomad4_exome. There are 30 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APRT	NM_000485.3	c.407T>C	p.Met136Thr	missense_variant	5/5	ENST00000378364.8
APRT	NM_001030018.2	c.401-128T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APRT	ENST00000378364.8	c.407T>C	p.Met136Thr	missense_variant	5/5	1	NM_000485.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248054 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134652

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1459600 Hom.: 1 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 726098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00116

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Adenine phosphoribosyltransferase deficiency Pathogenic:1 Other: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	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

APRT deficiency, Japanese type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.99	D;.
Vest4		0.74
MutPred		0.86		Loss of helix (P = 0.2662);.;
MVP		0.97
MPC		0.66
ClinPred		0.96	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.68

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: rs28999113; hg19: chr16-88876242;