rs4581

chr17-66214639-C-Achr17-66214639-C-Gchr17-66214639-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000042.3(APOH):c.796G>T(p.Val266Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,608,964 control chromosomes in the GnomAD database, including 85,022 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.36 (11892 hom., cov: 32)
  • Exomes 𝑓: 0.29 (73130 hom.)
• Consequence: APOH NM_000042.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.214

Genes affected

APOH (HGNC:616): (apolipoprotein H) Apolipoprotein H, also known as beta-2-glycoprotein I, is a component of circulating plasma lipoproteins. It has been implicated in a variety of physiologic pathways including lipoprotein metabolism, coagulation, hemostasis, and the production of antiphospholipid autoantibodies. APOH may be a required cofactor for anionic phospholipid binding by the antiphospholipid autoantibodies found in sera of many patients with lupus and primary antiphospholipid syndrome (APS). The anti-beta (2) glycoprotein I antibodies from APS patients, mediate inhibition of activated protein C which has anticoagulant properties. Because beta-2-GPI is the main autoantigen in patients with APS, the disruption of this pathway by autoantibodies may be an important mechanism for thrombosis in patients with APS.[provided by RefSeq, Dec 2019]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.019869E-7).
• BP6: Variant 17-66214639-C-A is Benign according to our data. Variant chr17-66214639-C-A is described in ClinVar as [Benign]. Clinvar id is 16042.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOH	NM_000042.3	c.796G>T	p.Val266Leu	missense_variant	7/8	ENST00000205948.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOH	ENST00000205948.11	c.796G>T	p.Val266Leu	missense_variant	7/8	1	NM_000042.3	P1
APOH	ENST00000585162.1	c.257+2149G>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55155 AN: 151794 Hom.: 11867 Cov.: 32

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.566

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.340

GnomAD3 exomes AF: 0.376 AC: 93812 AN: 249772 Hom.: 21980 AF XY: 0.370 AC XY: 49981 AN XY: 135096

Gnomad AFR exome AF: 0.520

Gnomad AMR exome AF: 0.553

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.769

Gnomad SAS exome AF: 0.549

Gnomad FIN exome AF: 0.249

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.287 AC: 418354 AN: 1457052 Hom.: 73130 Cov.: 33 AF XY: 0.293 AC XY: 212258 AN XY: 725110

Gnomad4 AFR exome AF: 0.530

Gnomad4 AMR exome AF: 0.546

Gnomad4 ASJ exome AF: 0.247

Gnomad4 EAS exome AF: 0.772

Gnomad4 SAS exome AF: 0.551

Gnomad4 FIN exome AF: 0.254

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.319

GnomAD4 genome AF: 0.364 AC: 55229 AN: 151912 Hom.: 11892 Cov.: 32 AF XY: 0.373 AC XY: 27665 AN XY: 74258

Gnomad4 AFR AF: 0.512

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.249

Gnomad4 EAS AF: 0.759

Gnomad4 SAS AF: 0.565

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.348

Alfa AF: 0.265 Hom.: 12015

Bravo AF: 0.385

TwinsUK AF: 0.232 AC: 861

ALSPAC AF: 0.237 AC: 913

ESP6500AA AF: 0.510 AC: 2245

ESP6500EA AF: 0.238 AC: 2043

ExAC AF: 0.374 AC: 45380

Asia WGS AF: 0.629 AC: 2183 AN: 3478

EpiCase AF: 0.233

EpiControl AF: 0.230

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

APOH POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

May 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.4
Dann	Benign	0.84
DEOGEN2	Benign	0.090	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	9.0e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.58	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.022
Sift	Benign	0.67	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.053
MutPred		0.23		Loss of catalytic residue at V266 (P = 0.069);
MPC		0.15
ClinPred		0.0020	T
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.074
gMVP		0.40

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: rs4581; hg19: chr17-64210757;