10-70884011-AGG-CACCCATGGTGAGCAC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000281.4(PCBD1):c.252_254delinsGTGCTCACCATGGGTG(p.Leu85CysfsTer32) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G84G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCBD1 NM_000281.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.90

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-70884011-AGG-CACCCATGGTGAGCAC is Pathogenic according to our data. Variant chr10-70884011-AGG-CACCCATGGTGAGCAC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2640562.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCBD1	NM_000281.4	c.252_254delinsGTGCTCACCATGGGTG	p.Leu85CysfsTer32	frameshift_variant	4/4	ENST00000299299.4
PCBD1	NM_001289797.2	c.105_107delinsGTGCTCACCATGGGTG	p.Leu36CysfsTer32	frameshift_variant	4/4
PCBD1	NM_001323004.2	c.216+1139_216+1141delinsGTGCTCACCATGGGTG		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCBD1	ENST00000299299.4	c.252_254delinsGTGCTCACCATGGGTG	p.Leu85CysfsTer32	frameshift_variant	4/4	1	NM_000281.4	P1
SGPL1	ENST00000697988.1	c.571-9748_571-9746delinsCACCCATGGTGAGCAC		intron_variant
PCBD1	ENST00000493228.1	n.651_653delinsGTGCTCACCATGGGTG		non_coding_transcript_exon_variant	4/4	2
PCBD1	ENST00000493961.5	n.183+1139_183+1141delinsGTGCTCACCATGGGTG		intron_variant, non_coding_transcript_variant		2

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2022

PCBD1: PVS1 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-72643768;