chr12-12787104-G-T

Position:

• chr12-12787104-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030817.3(APOLD1):​c.199G>T​(p.Ala67Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000158 in 1,262,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: APOLD1 NM_030817.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.68

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24274126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOLD1	NM_030817.3	c.199G>T	p.Ala67Ser	missense_variant	2/2	ENST00000356591.5	NP_110444.3
APOLD1	NM_001130415.2	c.292G>T	p.Ala98Ser	missense_variant	2/2		NP_001123887.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOLD1	ENST00000356591.5	c.199G>T	p.Ala67Ser	missense_variant	2/2	1	NM_030817.3	ENSP00000348998.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000158 AC: 2 AN: 1262034 Hom.: 0 Cov.: 31 AF XY: 0.00000163 AC XY: 1 AN XY: 614232

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: 0.00

Gnomad4 OTH exome AF: 0.0000383

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 09, 2024

The c.292G>T (p.A98S) alteration is located in exon 2 (coding exon 2) of the APOLD1 gene. This alteration results from a G to T substitution at nucleotide position 292, causing the alanine (A) at amino acid position 98 to be replaced by a serine (S). 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	Benign	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0013	T;.
Eigen	Benign	0.041
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.090	N;N
REVEL	Benign	0.14
Sift	Benign	0.23	T;T
Sift4G	Uncertain	0.031	D;D
Polyphen		0.77	P;.
Vest4		0.23
MutPred		0.52		Gain of catalytic residue at V103 (P = 9e-04);.;
MVP		0.33
ClinPred		0.87	D
GERP RS		4.3
Varity_R		0.12
gMVP		0.66

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: rs1947135637; hg19: chr12-12940038;