10-70883697-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000281.4(PCBD1):c.*253T>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 0.0203 in 1,358,168 control chromosomes in the GnomAD database, including 325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (34 hom., cov: 32)
  • Exomes 𝑓: 0.021 (291 hom.)
• Consequence: PCBD1 NM_000281.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.171

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=-0.76).
• BP6: Variant 10-70883697-A-T is Benign according to our data. Variant chr10-70883697-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 300342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0161 (2447/152336) while in subpopulation NFE AF= 0.0229 (1559/68036). AF 95% confidence interval is 0.022. There are 34 homozygotes in gnomad4. There are 1233 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCBD1	NM_000281.4	c.*253T>A		3_prime_UTR_variant	4/4	ENST00000299299.4
PCBD1	NM_001289797.2	c.*253T>A		3_prime_UTR_variant	4/4
PCBD1	NM_001323004.2	c.217-1212T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCBD1	ENST00000299299.4	c.*253T>A		3_prime_UTR_variant	4/4	1	NM_000281.4	P1
SGPL1	ENST00000697988.1	c.571-10062A>T		intron_variant
PCBD1	ENST00000493961.5	n.184-1212T>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2450 AN: 152218 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0144

GnomAD4 exome AF: 0.0209 AC: 25150 AN: 1205832 Hom.: 291 Cov.: 29 AF XY: 0.0204 AC XY: 11850 AN XY: 580374

Gnomad4 AFR exome AF: 0.00361

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.00737

Gnomad4 EAS exome AF: 0.0000704

Gnomad4 SAS exome AF: 0.00516

Gnomad4 FIN exome AF: 0.0320

Gnomad4 NFE exome AF: 0.0232

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0161 AC: 2447 AN: 152336 Hom.: 34 Cov.: 32 AF XY: 0.0166 AC XY: 1233 AN XY: 74488

Gnomad4 AFR AF: 0.00467

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0387

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00494 Hom.: 2

Bravo AF: 0.0141

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 29, 2019

- -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	9.0
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs77029400; hg19: chr10-72643454;