chr16-88809834-A-G

Variant names:

• chr16-88809834-A-G
• rs28999113
• NM_000485.3:c.407T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PM1 PP2 PP3_Strong PP5_Moderate 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 (★). 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 criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 6.78
• Publications: 16 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000485.3
• 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.
• 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 VariationId is 18296.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 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 GnomAdExome4. There are 30 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APRT	NM_000485.3	MANE Select	c.407T>C	p.Met136Thr	missense	Exon 5 of 5	NP_000476.1
	APRT	NM_001030018.2		c.401-128T>C		intron	N/A	NP_001025189.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APRT	ENST00000378364.8	TSL:1 MANE Select	c.407T>C	p.Met136Thr	missense	Exon 5 of 5	ENSP00000367615.3
	APRT	ENST00000563655.5	TSL:5	c.326T>C	p.Met109Thr	missense	Exon 4 of 4	ENSP00000456012.1
	APRT	ENST00000569616.1	TSL:5	c.471T>C	p.His157His	synonymous	Exon 5 of 5	ENSP00000455692.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248054 AF XY: 0.00000743

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00116 AC: 46 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111828

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Adenine phosphoribosyltransferase deficiency Pathogenic:2 Other:1

Mar 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2020

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

APRT deficiency, Japanese type Pathogenic:1

Nov 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.6	L
PhyloP100		6.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	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
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs28999113; hg19: chr16-88876242;