chr12-12787094-C-A

Position:

• chr12-12787094-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030817.3(APOLD1):​c.189C>A​(p.Ser63Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,253,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: APOLD1 NM_030817.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.181

Genes affected

APOLD1 (HGNC:25268): (apolipoprotein L domain containing 1) APOLD1 is an endothelial cell early response protein that may play a role in regulation of endothelial cell signaling and vascular function (Regard et al., 2004 [PubMed 15102925]).[supplied by OMIM, Dec 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3865632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOLD1	NM_030817.3	c.189C>A	p.Ser63Arg	missense_variant	2/2	ENST00000356591.5	NP_110444.3
APOLD1	NM_001130415.2	c.282C>A	p.Ser94Arg	missense_variant	2/2		NP_001123887.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOLD1	ENST00000356591.5	c.189C>A	p.Ser63Arg	missense_variant	2/2	1	NM_030817.3	ENSP00000348998.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000558 AC: 7 AN: 1253996 Hom.: 0 Cov.: 31 AF XY: 0.00000328 AC XY: 2 AN XY: 609598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000684

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.282C>A (p.S94R) alteration is located in exon 2 (coding exon 2) of the APOLD1 gene. This alteration results from a C to A substitution at nucleotide position 282, causing the serine (S) at amino acid position 94 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T;.
Eigen	Benign	0.094
Eigen_PC	Benign	-0.032
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		1.0	D;.
Vest4		0.29
MutPred		0.66		Gain of catalytic residue at G90 (P = 0);.;
MVP		0.49
ClinPred		0.98	D
GERP RS		2.4
Varity_R		0.40
gMVP		0.88

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: rs1457257025; hg19: chr12-12940028;