10-70883697-A-T

Variant names:

• chr10-70883697-A-T
• rs77029400
• NM_000281.4:c.*253T>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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: ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 10-70883697-A-T is Benign according to our data. Variant chr10-70883697-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

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.*253T>A		3_prime_UTR	Exon 4 of 4	NP_000272.1	P61457
	PCBD1	NM_001289797.2		c.*253T>A		3_prime_UTR	Exon 4 of 4	NP_001276726.1
	PCBD1	NM_001323004.2		c.217-1212T>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.*253T>A		3_prime_UTR	Exon 4 of 4	ENSP00000299299.3	P61457
	PCBD1	ENST00000875522.1		c.*253T>A		3_prime_UTR	Exon 4 of 4	ENSP00000545581.1
	PCBD1	ENST00000875521.1		c.*253T>A		3_prime_UTR	Exon 4 of 4	ENSP00000545580.1

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

African (AFR) AF: 0.00361 AC: 96 AN: 26604

American (AMR) AF: 0.0105 AC: 184 AN: 17574

Ashkenazi Jewish (ASJ) AF: 0.00737 AC: 123 AN: 16698

East Asian (EAS) AF: 0.0000704 AC: 2 AN: 28400

South Asian (SAS) AF: 0.00516 AC: 302 AN: 58540

European-Finnish (FIN) AF: 0.0320 AC: 721 AN: 22534

Middle Eastern (MID) AF: 0.00524 AC: 17 AN: 3244

European-Non Finnish (NFE) AF: 0.0232 AC: 22836 AN: 983410

Other (OTH) AF: 0.0178 AC: 869 AN: 48828

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

African (AFR) AF: 0.00467 AC: 194 AN: 41570

American (AMR) AF: 0.0125 AC: 192 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4824

European-Finnish (FIN) AF: 0.0387 AC: 411 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0229 AC: 1559 AN: 68036

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.00494 Hom.: 2

Bravo AF: 0.0141

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.0
DANN	Benign	0.87
PhyloP100		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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

dbSNP: rs77029400; hg19: chr10-72643454;