NM_000281.4:c.*36G>A

Variant names:

• chr10-70883914-C-T
• rs9712
• NM_000281.4:c.*36G>A

Variant summary

Our verdict is Benign. The variant received -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:4
• Conservation: PhyloP100: -0.411
• Publications: 15 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: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000281.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCBD1	NM_000281.4	MANE Select	c.*36G>A		3_prime_UTR	Exon 4 of 4	NP_000272.1	P61457
	PCBD1	NM_001289797.2		c.*36G>A		3_prime_UTR	Exon 4 of 4	NP_001276726.1
	PCBD1	NM_001323004.2		c.216+1238G>A		intron	N/A	NP_001309933.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCBD1	ENST00000299299.4	TSL:1 MANE Select	c.*36G>A		3_prime_UTR	Exon 4 of 4	ENSP00000299299.3	P61457
	PCBD1	ENST00000875522.1		c.*36G>A		3_prime_UTR	Exon 4 of 4	ENSP00000545581.1
	PCBD1	ENST00000875521.1		c.*36G>A		3_prime_UTR	Exon 4 of 4	ENSP00000545580.1

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

GnomAD2 exomes AF: 0.768 AC: 174802 AN: 227516 AF XY: 0.772

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 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

African (AFR) AF: 0.745 AC: 24822 AN: 33310

American (AMR) AF: 0.760 AC: 32365 AN: 42590

Ashkenazi Jewish (ASJ) AF: 0.755 AC: 19509 AN: 25836

East Asian (EAS) AF: 0.800 AC: 31534 AN: 39420

South Asian (SAS) AF: 0.852 AC: 71104 AN: 83422

European-Finnish (FIN) AF: 0.803 AC: 42160 AN: 52522

Middle Eastern (MID) AF: 0.732 AC: 4179 AN: 5708

European-Non Finnish (NFE) AF: 0.741 AC: 817545 AN: 1103646

Other (OTH) AF: 0.749 AC: 44845 AN: 59840

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

African (AFR) AF: 0.741 AC: 30699 AN: 41408

American (AMR) AF: 0.757 AC: 11558 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 2579 AN: 3458

East Asian (EAS) AF: 0.782 AC: 4028 AN: 5152

South Asian (SAS) AF: 0.857 AC: 4118 AN: 4806

European-Finnish (FIN) AF: 0.809 AC: 8578 AN: 10598

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.740 AC: 50303 AN: 67966

Other (OTH) AF: 0.732 AC: 1546 AN: 2112

Alfa AF: 0.742 Hom.: 18584

Bravo AF: 0.741

Asia WGS AF: 0.840 AC: 2920 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Pterin-4 alpha-carbinolamine dehydratase 1 deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.7
DANN	Benign	0.71
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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