10-70883914-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000281.4(PCBD1):c.*36G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 1,598,278 control chromosomes in the GnomAD database, including 453,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43064 hom., cov: 31)
  • Exomes 𝑓: 0.75 (410361 hom.)
• Consequence: PCBD1 NM_000281.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.411

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 10-70883914-C-T is Benign according to our data. Variant chr10-70883914-C-T is described in ClinVar as [Benign]. Clinvar id is 300345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCBD1	NM_000281.4	c.*36G>A		3_prime_UTR_variant	4/4	ENST00000299299.4
PCBD1	NM_001289797.2	c.*36G>A		3_prime_UTR_variant	4/4
PCBD1	NM_001323004.2	c.216+1238G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCBD1	ENST00000299299.4	c.*36G>A		3_prime_UTR_variant	4/4	1	NM_000281.4	P1
SGPL1	ENST00000697988.1	c.571-9845C>T		intron_variant
PCBD1	ENST00000493961.5	n.183+1238G>A		intron_variant, non_coding_transcript_variant		2
PCBD1	ENST00000493228.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.751 AC: 114110 AN: 151866 Hom.: 43027 Cov.: 31

Gnomad AFR AF: 0.741

Gnomad AMI AF: 0.627

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.746

Gnomad EAS AF: 0.782

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.740

Gnomad OTH AF: 0.730

GnomAD3 exomes AF: 0.768 AC: 174802 AN: 227516 Hom.: 67272 AF XY: 0.772 AC XY: 94251 AN XY: 122098

Gnomad AFR exome AF: 0.739

Gnomad AMR exome AF: 0.764

Gnomad ASJ exome AF: 0.756

Gnomad EAS exome AF: 0.775

Gnomad SAS exome AF: 0.858

Gnomad FIN exome AF: 0.806

Gnomad NFE exome AF: 0.743

Gnomad OTH exome AF: 0.750

GnomAD4 exome AF: 0.752 AC: 1088063 AN: 1446294 Hom.: 410361 Cov.: 54 AF XY: 0.755 AC XY: 541645 AN XY: 717606

Gnomad4 AFR exome AF: 0.745

Gnomad4 AMR exome AF: 0.760

Gnomad4 ASJ exome AF: 0.755

Gnomad4 EAS exome AF: 0.800

Gnomad4 SAS exome AF: 0.852

Gnomad4 FIN exome AF: 0.803

Gnomad4 NFE exome AF: 0.741

Gnomad4 OTH exome AF: 0.749

GnomAD4 genome AF: 0.751 AC: 114203 AN: 151984 Hom.: 43064 Cov.: 31 AF XY: 0.759 AC XY: 56384 AN XY: 74296

Gnomad4 AFR AF: 0.741

Gnomad4 AMR AF: 0.757

Gnomad4 ASJ AF: 0.746

Gnomad4 EAS AF: 0.782

Gnomad4 SAS AF: 0.857

Gnomad4 FIN AF: 0.809

Gnomad4 NFE AF: 0.740

Gnomad4 OTH AF: 0.732

Alfa AF: 0.744 Hom.: 15483

Bravo AF: 0.741

Asia WGS AF: 0.840 AC: 2920 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pterin-4 alpha-carbinolamine dehydratase 1 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.7
Dann	Benign	0.71

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

Other links and lift over

dbSNP: rs9712; hg19: chr10-72643671; COSMIC: COSV54738622; COSMIC: COSV54738622;