rs12769766

Variant names:

• chr10-70887028-T-A
• rs12769766
• NM_000281.4:c.4-1099A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-70887028-T-A
• chr10-70887028-T-G

Variant summary

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

The NM_000281.4(PCBD1):​c.4-1099A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,100 control chromosomes in the GnomAD database, including 1,242 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 0.11 (1242 hom., cov: 32)
• Consequence: PCBD1 NM_000281.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.883
• Publications: 1 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCBD1	NM_000281.4	c.4-1099A>T		intron_variant	Intron 1 of 3	ENST00000299299.4	NP_000272.1
PCBD1	NM_001323004.2	c.4-1099A>T		intron_variant	Intron 1 of 3		NP_001309933.1
PCBD1	NM_001289797.2	c.-145+825A>T		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.4-1099A>T		intron_variant	Intron 1 of 3	1	NM_000281.4	ENSP00000299299.3
SGPL1	ENST00000697988.1	c.571-6731T>A		intron_variant	Intron 8 of 8			ENSP00000513492.1
SGPL1	ENST00000697990.2	c.464+18595T>A		intron_variant	Intron 7 of 7			ENSP00000520631.1
PCBD1	ENST00000493228.1	n.402+825A>T		intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17450 AN: 151982 Hom.: 1242 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.0864

Gnomad SAS AF: 0.0808

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.119

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

GnomAD4 genome AF: 0.115 AC: 17442 AN: 152100 Hom.: 1242 Cov.: 32 AF XY: 0.111 AC XY: 8271 AN XY: 74354

African (AFR) AF: 0.0407 AC: 1688 AN: 41508

American (AMR) AF: 0.103 AC: 1571 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 539 AN: 3468

East Asian (EAS) AF: 0.0858 AC: 444 AN: 5172

South Asian (SAS) AF: 0.0798 AC: 385 AN: 4822

European-Finnish (FIN) AF: 0.149 AC: 1573 AN: 10572

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10873 AN: 67952

Other (OTH) AF: 0.118 AC: 250 AN: 2112

Alfa AF: 0.0737 Hom.: 94

Bravo AF: 0.109

Asia WGS AF: 0.0740 AC: 260 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.85
DANN	Benign	0.84
PhyloP100		-0.88
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: rs12769766; hg19: chr10-72646785;