chrX-85051474-G-A

Position:

• chrX-85051474-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_198450.6(APOOL):​c.206G>A​(p.Arg69His) variant causes a missense change. The variant allele was found at a frequency of 0.00000364 in 1,097,554 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 0 hem.)
• Consequence: APOOL NM_198450.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34

Genes affected

APOOL (HGNC:24009): (apolipoprotein O like) This gene encodes a protein which contains an apolipoprotein O superfamily domain. This domain is found on proteins in circulating lipoprotein complexes. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOOL	NM_198450.6	c.206G>A	p.Arg69His	missense_variant	3/9	ENST00000373173.7	NP_940852.3
APOOL	XM_017029272.2	c.206G>A	p.Arg69His	missense_variant	3/9		XP_016884761.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOOL	ENST00000373173.7	c.206G>A	p.Arg69His	missense_variant	3/9	1	NM_198450.6	ENSP00000362268	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097554 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363168

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: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

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

May 13, 2024

The c.206G>A (p.R69H) alteration is located in exon 3 (coding exon 3) of the APOOL gene. This alteration results from a G to A substitution at nucleotide position 206, causing the arginine (R) at amino acid position 69 to be replaced by a histidine (H). 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	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-4.2	D;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.038	D;.;.
Sift4G	Uncertain	0.044	D;D;D
Polyphen		0.35	B;.;.
Vest4		0.80
MutPred		0.95		Loss of MoRF binding (P = 0.0793);.;Loss of MoRF binding (P = 0.0793);
MVP		0.99
MPC		0.030
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.50
gMVP		0.90

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: rs1922775615; hg19: chrX-84306480;