NM_032906.5:c.-97G>A

Variant names:

• chr4-88523797-C-T
• rs869025323
• NM_032906.5:c.-97G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_032906.5(PYURF):​c.-97G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PYURF NM_032906.5 upstream_gene
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.92
• Publications: 2 publications found

Genes affected

PYURF (HGNC:44317): (PIGY upstream open reading frame) The product of this gene, which is well-conserved, is encoded by the same bicistronic transcript that encodes phosphatidylinositol glycan anchor biosynthesis, class Y, but the two proteins are unrelated. This gene represents the protein encoded by the upstream open reading frame, while the protein encoded by the downstream open reading frame is represented by GeneID:84992. [provided by RefSeq, Aug 2012]

PIGY (HGNC:28213): (phosphatidylinositol glycan anchor biosynthesis class Y) The protein encoded by this gene is part of the GPI-N-acetylglucosaminyltransferase (GIP-GnT) complex which initiates the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is synthesized in the endoplasmic reticulum and serves as an anchor for many surface proteins. Proteins containing GPI anchors can have an important role in cell-cell interactions. The transcript for this gene is bicistronic. The downstream open reading frame encodes this GPI-GnT complex protein, while the upstream open reading frame encodes a protein with unknown function, as represented by GeneID:100996939. [provided by RefSeq, Aug 2012]

HERC3 (HGNC:4876): (HECT and RLD domain containing E3 ubiquitin protein ligase 3) This gene encodes a member the HERC ubiquitin ligase family. The encoded protein is located in the cytosol and binds ubiquitin via a HECT domain. Mutations in this gene have been associated with colorectal and gastric carcinomas. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2012]

PIGY-DT (HGNC:54080): (PIGY divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-88523797-C-T is Pathogenic according to our data. Variant chr4-88523797-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 222025.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032906.5. 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
	PYURF	NM_032906.5	MANE Select	c.-97G>A		upstream_gene	N/A	NP_116295.1	Q96I23
	PIGY	NM_001042616.3	MANE Select	c.-540G>A		upstream_gene	N/A	NP_001036081.1	Q3MUY2
	HERC3	NM_001375482.1		c.-223C>T		upstream_gene	N/A	NP_001362411.1	H0Y8G9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYURF	ENST00000273968.5	TSL:1 MANE Select	c.-97G>A		upstream_gene	N/A	ENSP00000273968.4	Q96I23
	PIGY	ENST00000527353.2	TSL:6 MANE Select	c.-540G>A		upstream_gene	N/A	ENSP00000432688.1	Q3MUY2
	HERC3	ENST00000512194.2	TSL:5	c.-361C>T		upstream_gene	N/A	ENSP00000421021.2	H0Y8G9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1044586 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 511920

African (AFR) AF: 0.00 AC: 0 AN: 19894

American (AMR) AF: 0.00 AC: 0 AN: 12886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16206

East Asian (EAS) AF: 0.00 AC: 0 AN: 28088

South Asian (SAS) AF: 0.00 AC: 0 AN: 53212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3080

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836660

Other (OTH) AF: 0.00 AC: 0 AN: 44876

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hyperphosphatasia with intellectual disability syndrome 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Uncertain	0.98
PhyloP100		2.9
PromoterAI		-0.77	Under-expression

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: rs869025323; hg19: chr4-89444948;