chr10-70883979-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000281.4(PCBD1):ā€‹c.286A>Gā€‹(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 (ā˜…). Synonymous variant affecting the same amino acid position (i.e. I96I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

PCBD1
NM_000281.4 missense

Scores

8
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.64
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]

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ACMG classification

Classification made for transcript

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
PCBD1NM_000281.4 linkuse as main transcriptc.286A>G p.Ile96Val missense_variant 4/4 ENST00000299299.4
PCBD1NM_001289797.2 linkuse as main transcriptc.139A>G p.Ile47Val missense_variant 4/4
PCBD1NM_001323004.2 linkuse as main transcriptc.216+1173A>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PCBD1ENST00000299299.4 linkuse as main transcriptc.286A>G p.Ile96Val missense_variant 4/41 NM_000281.4 P1
SGPL1ENST00000697988.1 linkuse as main transcriptc.571-9780T>C intron_variant
PCBD1ENST00000493228.1 linkuse as main transcriptn.685A>G non_coding_transcript_exon_variant 4/42
PCBD1ENST00000493961.5 linkuse as main transcriptn.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
show subpopulations
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
LINK: link

Submissions by phenotype

Pterin-4 alpha-carbinolamine dehydratase 1 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 03, 2022In 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

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

Other links and lift over

dbSNP: rs1846540054; hg19: chr10-72643736; API