rs12769766

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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.

• 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/exons	MANE	Protein	UniProt
PCBD1	NM_000281.4	c.4-1099A>T		intron_variant		ENST00000299299.4	NP_000272.1
PCBD1	NM_001289797.2	c.-145+825A>T		intron_variant			NP_001276726.1
PCBD1	NM_001323004.2	c.4-1099A>T		intron_variant			NP_001309933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCBD1	ENST00000299299.4	c.4-1099A>T		intron_variant		1	NM_000281.4	ENSP00000299299	P1
SGPL1	ENST00000697988.1	c.571-6731T>A		intron_variant				ENSP00000513492
PCBD1	ENST00000493228.1	n.402+825A>T		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR AF: 0.0407

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.0858

Gnomad4 SAS AF: 0.0798

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.118

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

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

Other links and lift over

dbSNP: rs12769766; hg19: chr10-72646785;