10-70883979-T-C

Variant summary

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

The NM_000281.4(PCBD1):c.286A>G(p.Ile96Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,808 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I96I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PCBD1 NM_000281.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.64

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31371367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCBD1	NM_000281.4	c.286A>G	p.Ile96Val	missense_variant	4/4	ENST00000299299.4
PCBD1	NM_001289797.2	c.139A>G	p.Ile47Val	missense_variant	4/4
PCBD1	NM_001323004.2	c.216+1173A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCBD1	ENST00000299299.4	c.286A>G	p.Ile96Val	missense_variant	4/4	1	NM_000281.4	P1
SGPL1	ENST00000697988.1	c.571-9780T>C		intron_variant
PCBD1	ENST00000493228.1	n.685A>G		non_coding_transcript_exon_variant	4/4	2
PCBD1	ENST00000493961.5	n.183+1173A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461808 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727192

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 03, 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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PCBD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 96 of the PCBD1 protein (p.Ile96Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	23
Dann	Benign	0.96
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.49
Sift	Benign	0.044	D
Sift4G	Uncertain	0.039	D
Polyphen		0.19	B
Vest4		0.23
MutPred		0.68		Gain of disorder (P = 0.1106);
MVP		0.77
MPC		0.22
ClinPred		0.51	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.49

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: rs1846540054; hg19: chr10-72643736;