rs12218438

Variant names:

• chr10-70886580-C-T
• rs12218438
• NM_000281.4:c.4-651G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000281.4(PCBD1):​c.4-651G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0726 in 152,274 control chromosomes in the GnomAD database, including 640 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.073 (640 hom., cov: 33)
• Consequence: PCBD1 NM_000281.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0780
• Publications: 7 publications found

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]

SGPL1 Gene-Disease associations (from GenCC):

• nephrotic syndrome 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCBD1	NM_000281.4	c.4-651G>A		intron_variant	Intron 1 of 3	ENST00000299299.4	NP_000272.1
PCBD1	NM_001323004.2	c.4-651G>A		intron_variant	Intron 1 of 3		NP_001309933.1
PCBD1	NM_001289797.2	c.-144-651G>A		intron_variant	Intron 1 of 3		NP_001276726.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCBD1	ENST00000299299.4	c.4-651G>A		intron_variant	Intron 1 of 3	1	NM_000281.4	ENSP00000299299.3
SGPL1	ENST00000697988.1	c.571-7179C>T		intron_variant	Intron 8 of 8			ENSP00000513492.1
SGPL1	ENST00000697990.2	c.464+18147C>T		intron_variant	Intron 7 of 7			ENSP00000520631.1
PCBD1	ENST00000493228.1	n.403-651G>A		intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.0726 AC: 11053 AN: 152156 Hom.: 642 Cov.: 33

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.0930

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0599

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0800

Gnomad OTH AF: 0.0785

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0726 AC: 11052 AN: 152274 Hom.: 640 Cov.: 33 AF XY: 0.0743 AC XY: 5528 AN XY: 74448

African (AFR) AF: 0.0189 AC: 785 AN: 41576

American (AMR) AF: 0.0932 AC: 1425 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 373 AN: 3472

East Asian (EAS) AF: 0.300 AC: 1550 AN: 5164

South Asian (SAS) AF: 0.123 AC: 596 AN: 4828

European-Finnish (FIN) AF: 0.0599 AC: 636 AN: 10612

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.0800 AC: 5441 AN: 68016

Other (OTH) AF: 0.0791 AC: 167 AN: 2110

Alfa AF: 0.0791 Hom.: 1186

Bravo AF: 0.0746

Asia WGS AF: 0.230 AC: 797 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.23
DANN	Benign	0.72
PhyloP100		-0.078
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12218438; hg19: chr10-72646337;