10-70884006-C-A

Position:

chr10-70884006-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000281.4(PCBD1):c.259G>T(p.Glu87Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000458 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

PCBD1
NM_000281.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.60

Variant links:

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]

PCBD1 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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. Fraction of 0.178 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-70884006-C-A is Pathogenic according to our data. Variant chr10-70884006-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PCBD1	NM_000281.4 linkuse as main transcript	c.259G>T	p.Glu87Ter	stop_gained	4/4	ENST00000299299.4	NP_000272.1
PCBD1	NM_001289797.2 linkuse as main transcript	c.112G>T	p.Glu38Ter	stop_gained	4/4		NP_001276726.1
PCBD1	NM_001323004.2 linkuse as main transcript	c.216+1146G>T		intron_variant			NP_001309933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PCBD1	ENST00000299299.4 linkuse as main transcript	c.259G>T	p.Glu87Ter	stop_gained	4/4	1	NM_000281.4	ENSP00000299299	P1
SGPL1	ENST00000697988.1 linkuse as main transcript	c.571-9753C>A		intron_variant				ENSP00000513492
PCBD1	ENST00000493228.1 linkuse as main transcript	n.658G>T		non_coding_transcript_exon_variant	4/4	2
PCBD1	ENST00000493961.5 linkuse as main transcript	n.183+1146G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

251266

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000451

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000980

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pterin-4 alpha-carbinolamine dehydratase 1 deficiency

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The PCBD1 c.259G>T (p.Glu87Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. This variant has been reported in at least two studies in which it is found in a total of three individuals with BH4-deficient hyperphenylalaninemia, including two siblings of Ashkenazi Jewish descent who were homozygous for the variant and another individual who was compound heterozygous for the variant and a missense variant (Citron et al. 1993; ThÃ¶ny et al. 1998). The p.Glu87Ter variant was found in a heterozygous state in both unaffected parents of the homozygous siblings and in the unaffected father of the compound heterozygote. The variant was also found in a heterozygous state in a centenarian from a longevity study (Freudenberg-Hua et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression of the p.Glu87Ter variant in cell lines revealed little to no residual dehydratase activity, with most of the protein found in the insoluble fraction and no detectable PCBD1 protein. The residual mutant protein was still able to bind substrate with a Km that did not significantly differ from wild type (Johnen et al. 1995; ThÃ¶ny et al. 1998; FerrÃ¨ et al. 2014). Based on the evidence and the potential impact of stop-gained variants, the p.Glu87Ter variant is classified as likely pathogenic for BH4-deficient hyperphenylalaninemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change creates a premature translational stop signal (p.Glu87) in the PCBD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the PCBD1 protein. This variant is present in population databases (rs104894172, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with clinical features of biopterin deficient hyperphenylalanemia (PMID: 8352282, 9585615). This variant is also known as E86X . ClinVar contains an entry for this variant (Variation ID: 16795). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PCBD1 function (PMID: 8618906). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the PCBD1 protein in which other variant(s) (p.Gln98) have been determined to be pathogenic (PMID: 24204001). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1998	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.92

MutationTaster

Benign

1.0

Vest4

0.27

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over