rs121913014

Variant names:

• chr10-70884029-G-A
• rs121913014
• NM_000281.4:c.236C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000281.4(PCBD1):​c.236C>T​(p.Thr79Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCBD1 NM_000281.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.32
• Publications: 3 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

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.236C>T	p.Thr79Ile	missense	Exon 4 of 4	NP_000272.1	P61457
	PCBD1	NM_001289797.2		c.89C>T	p.Thr30Ile	missense	Exon 4 of 4	NP_001276726.1
	PCBD1	NM_001323004.2		c.216+1123C>T		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.236C>T	p.Thr79Ile	missense	Exon 4 of 4	ENSP00000299299.3	P61457
	PCBD1	ENST00000875522.1		c.296C>T	p.Thr99Ile	missense	Exon 4 of 4	ENSP00000545581.1
	PCBD1	ENST00000875521.1		c.248C>T	p.Thr83Ile	missense	Exon 4 of 4	ENSP00000545580.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Pterin-4 alpha-carbinolamine dehydratase 1 deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		9.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.98		Loss of catalytic residue at T79 (P = 0.0226)
MVP		0.97
MPC		0.70
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.93
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs121913014; hg19: chr10-72643786;