rs552713157

Variant names:

• chr4-56435340-T-A
• rs552713157
• NM_002703.5:c.128+10A>T

Your query was ambiguous. Multiple possible variants found:

• chr4-56435340-T-A
• chr4-56435340-T-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_002703.5(PPAT):​c.128+10A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 148,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPAT NM_002703.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.47
• Publications: 0 publications found

Genes affected

PPAT (HGNC:9238): (phosphoribosyl pyrophosphate amidotransferase) The protein encoded by this gene is a member of the purine/pyrimidine phosphoribosyltransferase family. It is a regulatory allosteric enzyme that catalyzes the first step of de novo purine nucleotide biosythetic pathway. This gene and PAICS/AIRC gene, a bifunctional enzyme catalyzing steps six and seven of this pathway, are located in close proximity on chromosome 4, and divergently transcribed from an intergenic region. [provided by RefSeq, Mar 2011]

PAICS (HGNC:8587): (phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase) This gene encodes a bifunctional enzyme containing phosphoribosylaminoimidazole carboxylase activity in its N-terminal region and phosphoribosylaminoimidazole succinocarboxamide synthetase in its C-terminal region. It catalyzes steps 6 and 7 of purine biosynthesis. The gene is closely linked and divergently transcribed with a locus that encodes an enzyme in the same pathway, and transcription of the two genes is coordinately regulated. The human genome contains several pseudogenes of this gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PAICS Gene-Disease associations (from GenCC):

• PAICS deficiency

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-56435340-T-A is Benign according to our data. Variant chr4-56435340-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 726437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002703.5. 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
	PPAT	NM_002703.5	MANE Select	c.128+10A>T		intron	N/A	NP_002694.3
	PAICS	NM_001392010.1		c.1096-922T>A		intron	N/A	NP_001378939.1
	PAICS	NM_001392011.1		c.1012-922T>A		intron	N/A	NP_001378940.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPAT	ENST00000264220.6	TSL:1 MANE Select	c.128+10A>T		intron	N/A	ENSP00000264220.2	Q06203
	PAICS	ENST00000913768.1		c.-235T>A		5_prime_UTR	Exon 1 of 10	ENSP00000583827.1
	PPAT	ENST00000965522.1		c.128+10A>T		intron	N/A	ENSP00000635581.1

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 148234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000223

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247912 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00119 AC: 1430 AN: 1201498 Hom.: 0 Cov.: 33 AF XY: 0.00109 AC XY: 654 AN XY: 602712

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00125 AC: 34 AN: 27216

American (AMR) AF: 0.000144 AC: 6 AN: 41594

Ashkenazi Jewish (ASJ) AF: 0.000853 AC: 18 AN: 21106

East Asian (EAS) AF: 0.000605 AC: 19 AN: 31400

South Asian (SAS) AF: 0.000439 AC: 36 AN: 82008

European-Finnish (FIN) AF: 0.000109 AC: 5 AN: 45990

Middle Eastern (MID) AF: 0.00102 AC: 5 AN: 4906

European-Non Finnish (NFE) AF: 0.00138 AC: 1243 AN: 899232

Other (OTH) AF: 0.00133 AC: 64 AN: 48046

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 148360 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72448

African (AFR) AF: 0.0000248 AC: 1 AN: 40344

American (AMR) AF: 0.00 AC: 0 AN: 15026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3416

East Asian (EAS) AF: 0.00 AC: 0 AN: 4854

South Asian (SAS) AF: 0.000223 AC: 1 AN: 4482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67034

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.2
DANN	Benign	0.80
PhyloP100		-1.5
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs552713157; hg19: chr4-57301506;