10-70884002-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PM1 PM2 BP4_Strong BP6_Very_Strong BS1

The NM_000281.4(PCBD1):c.263G>A(p.Arg88Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,614,100 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). 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: 𝑓 0.00079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: PCBD1 NM_000281.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.35

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 Benign. Variant got -12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000281.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045114964).
• BP6: Variant 10-70884002-C-T is Benign according to our data. Variant chr10-70884002-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 242621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000788 (120/152274) while in subpopulation AFR AF= 0.00262 (109/41542). AF 95% confidence interval is 0.00222. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCBD1	NM_000281.4	c.263G>A	p.Arg88Gln	missense_variant	4/4	ENST00000299299.4
PCBD1	NM_001289797.2	c.116G>A	p.Arg39Gln	missense_variant	4/4
PCBD1	NM_001323004.2	c.216+1150G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCBD1	ENST00000299299.4	c.263G>A	p.Arg88Gln	missense_variant	4/4	1	NM_000281.4	P1
SGPL1	ENST00000697988.1	c.571-9757C>T		intron_variant
PCBD1	ENST00000493228.1	n.662G>A		non_coding_transcript_exon_variant	4/4	2
PCBD1	ENST00000493961.5	n.183+1150G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000275 AC: 69 AN: 251258 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135802

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1461826 Hom.: 1 Cov.: 35 AF XY: 0.000105 AC XY: 76 AN XY: 727206

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74458

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000767

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

PCBD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.045	T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.63
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		0.86	P
Vest4		0.60
MVP		0.93
MPC		0.24
ClinPred		0.063	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115117837; hg19: chr10-72643759;