10-70883952-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000281.4(PCBD1):c.313T>C(p.Ter105GlnextTer14) variant causes a stop lost change. The variant allele was found at a frequency of 0.0000123 in 1,461,378 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: PCBD1 NM_000281.4 stop_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.42

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-70883952-A-G is Pathogenic according to our data. Variant chr10-70883952-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428616.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.189829).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCBD1	NM_000281.4	c.313T>C	p.Ter105GlnextTer14	stop_lost	4/4	ENST00000299299.4
PCBD1	NM_001289797.2	c.166T>C	p.Ter56GlnextTer14	stop_lost	4/4
PCBD1	NM_001323004.2	c.216+1200T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCBD1	ENST00000299299.4	c.313T>C	p.Ter105GlnextTer14	stop_lost	4/4	1	NM_000281.4	P1
SGPL1	ENST00000697988.1	c.571-9807A>G		intron_variant
PCBD1	ENST00000493228.1	n.712T>C		non_coding_transcript_exon_variant	4/4	2
PCBD1	ENST00000493961.5	n.183+1200T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250456 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135338

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 SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461378 Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9 AN XY: 726886

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pterin-4 alpha-carbinolamine dehydratase 1 deficiency Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	research	National Reference Laboratory of Biochemistry, Pasteur Institute of Iran	Jan 01, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 05, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 428616). This protein extension has been observed in individual(s) with clinical features of biopterin-deficient hyperphenylalaninemia (PMID: 24133926, 27246466). This variant is present in population databases (rs770334825, gnomAD 0.003%). This sequence change disrupts the translational stop signal of the PCBD1 mRNA. It is expected to extend the length of the PCBD1 protein by 14 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	16
Dann	Benign	0.70
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	N
Vest4		0.010
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs770334825; hg19: chr10-72643709; COSMIC: COSV54738235; COSMIC: COSV54738235;