chr10-70884001-CC-TT

Variant names:

• chr10-70884001-CC-TT
• NM_000281.4:c.263_264delGGinsAA
• PCBD1 p.Arg88Gln

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000281.4(PCBD1):​c.263_264delGGinsAA​(p.Arg88Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R88W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCBD1 NM_000281.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.35
• Publications: 0 publications found

Genes affected

PCBD1 (HGNC:8646): (pterin-4 alpha-carbinolamine dehydratase 1) This gene encodes a member of the pterin-4-alpha-carbinolamine dehydratase family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. The encoded protein functions as both a dehydratase involved in tetrahydrobiopterin biosynthesis, and as a cofactor for HNF1A-dependent transcription. A deficiency of this enzyme leads to hyperphenylalaninemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

SGPL1 (HGNC:10817): (sphingosine-1-phosphate lyase 1) Enables sphinganine-1-phosphate aldolase activity. Involved in apoptotic signaling pathway; fatty acid metabolic process; and sphingolipid metabolic process. Located in endoplasmic reticulum. Implicated in nephrotic syndrome type 14. [provided by Alliance of Genome Resources, Apr 2022]

SGPL1 Gene-Disease associations (from GenCC):

• nephrotic syndrome 14

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000281.4

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000281.4. 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
	PCBD1	NM_000281.4	MANE Select	c.263_264delGGinsAA	p.Arg88Gln	missense	N/A	NP_000272.1	P61457
	PCBD1	NM_001289797.2		c.116_117delGGinsAA	p.Arg39Gln	missense	N/A	NP_001276726.1
	PCBD1	NM_001323004.2		c.216+1150_216+1151delGGinsAA		intron	N/A	NP_001309933.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCBD1	ENST00000299299.4	TSL:1 MANE Select	c.263_264delGGinsAA	p.Arg88Gln	missense	N/A	ENSP00000299299.3	P61457
	PCBD1	ENST00000875522.1		c.323_324delGGinsAA	p.Arg108Gln	missense	N/A	ENSP00000545581.1
	PCBD1	ENST00000875521.1		c.275_276delGGinsAA	p.Arg92Gln	missense	N/A	ENSP00000545580.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-72643758;