NM_000281.4:c.307A>G

Variant names:

• chr10-70883958-T-C
• NM_000281.4:c.307A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000281.4(PCBD1):​c.307A>G​(p.Met103Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M103K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PCBD1 NM_000281.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10854855).

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.307A>G	p.Met103Val	missense	Exon 4 of 4	NP_000272.1	P61457
	PCBD1	NM_001289797.2		c.160A>G	p.Met54Val	missense	Exon 4 of 4	NP_001276726.1
	PCBD1	NM_001323004.2		c.216+1194A>G		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.307A>G	p.Met103Val	missense	Exon 4 of 4	ENSP00000299299.3	P61457
	PCBD1	ENST00000875522.1		c.367A>G	p.Met123Val	missense	Exon 4 of 4	ENSP00000545581.1
	PCBD1	ENST00000875521.1		c.319A>G	p.Met107Val	missense	Exon 4 of 4	ENSP00000545580.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Benign	0.51
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.70	N
PhyloP100		3.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.27
Sift	Benign	0.92	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.31
MutPred		0.38		Gain of relative solvent accessibility (P = 0.0098)
MVP		0.78
MPC		0.16
ClinPred		0.13	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.61
Mutation Taster		=74/26	polymorphism

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

hg19: chr10-72643715;