10-70884002-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

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 (★★).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

PCBD1
NM_000281.4 missense

Scores

4
9
6

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 7.35
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

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 rank MANE Protein UniProt
PCBD1NM_000281.4 linkc.263G>A p.Arg88Gln missense_variant Exon 4 of 4 ENST00000299299.4 NP_000272.1 P61457
PCBD1NM_001289797.2 linkc.116G>A p.Arg39Gln missense_variant Exon 4 of 4 NP_001276726.1 P61457
PCBD1NM_001323004.2 linkc.216+1150G>A intron_variant Intron 3 of 3 NP_001309933.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PCBD1ENST00000299299.4 linkc.263G>A p.Arg88Gln missense_variant Exon 4 of 4 1 NM_000281.4 ENSP00000299299.3 P61457

Frequencies

GnomAD3 genomes
AF:
0.000756
AC:
115
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 02, 2021This 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 20, 2025- -
PCBD1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 29, 2022This 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
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

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

Other links and lift over

dbSNP: rs115117837; hg19: chr10-72643759; API