17-66212167-C-G

Variant names:

• chr17-66212167-C-G
• rs1801690
• NM_000042.3:c.1004G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000042.3(APOH):​c.1004G>C​(p.Trp335Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0514 in 1,612,074 control chromosomes in the GnomAD database, including 2,408 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.040 (168 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2240 hom.)
• Consequence: APOH NM_000042.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.84
• Publications: 44 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011089236).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0644 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000042.3. 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
	APOH	NM_000042.3	MANE Select	c.1004G>C	p.Trp335Ser	missense	Exon 8 of 8	NP_000033.2	A0A384NKM6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOH	ENST00000205948.11	TSL:1 MANE Select	c.1004G>C	p.Trp335Ser	missense	Exon 8 of 8	ENSP00000205948.6	P02749
	APOH	ENST00000879124.1		c.1004G>C	p.Trp335Ser	missense	Exon 8 of 8	ENSP00000549183.1
	APOH	ENST00000879112.1		c.1001G>C	p.Trp334Ser	missense	Exon 8 of 8	ENSP00000549171.1

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 6161 AN: 151982 Hom.: 168 Cov.: 33

Gnomad AFR AF: 0.00868

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0313

Gnomad ASJ AF: 0.0387

Gnomad EAS AF: 0.0707

Gnomad SAS AF: 0.0511

Gnomad FIN AF: 0.0705

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0545

Gnomad OTH AF: 0.0363

GnomAD2 exomes AF: 0.0479 AC: 12020 AN: 251190 AF XY: 0.0492

Gnomad AFR exome AF: 0.00800

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0327

Gnomad EAS exome AF: 0.0667

Gnomad FIN exome AF: 0.0745

Gnomad NFE exome AF: 0.0555

Gnomad OTH exome AF: 0.0510

GnomAD4 exome AF: 0.0525 AC: 76641 AN: 1459974 Hom.: 2240 Cov.: 31 AF XY: 0.0528 AC XY: 38334 AN XY: 726334

African (AFR) AF: 0.00601 AC: 201 AN: 33462

American (AMR) AF: 0.0203 AC: 905 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0322 AC: 842 AN: 26122

East Asian (EAS) AF: 0.0872 AC: 3459 AN: 39658

South Asian (SAS) AF: 0.0462 AC: 3976 AN: 86152

European-Finnish (FIN) AF: 0.0733 AC: 3913 AN: 53398

Middle Eastern (MID) AF: 0.0413 AC: 238 AN: 5766

European-Non Finnish (NFE) AF: 0.0545 AC: 60487 AN: 1110366

Other (OTH) AF: 0.0434 AC: 2620 AN: 60360

GnomAD4 genome AF: 0.0405 AC: 6160 AN: 152100 Hom.: 168 Cov.: 33 AF XY: 0.0409 AC XY: 3039 AN XY: 74338

African (AFR) AF: 0.00865 AC: 359 AN: 41504

American (AMR) AF: 0.0313 AC: 478 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0387 AC: 134 AN: 3466

East Asian (EAS) AF: 0.0703 AC: 364 AN: 5176

South Asian (SAS) AF: 0.0511 AC: 246 AN: 4810

European-Finnish (FIN) AF: 0.0705 AC: 745 AN: 10560

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.0546 AC: 3711 AN: 67994

Other (OTH) AF: 0.0364 AC: 77 AN: 2116

Alfa AF: 0.0518 Hom.: 165

Bravo AF: 0.0351

TwinsUK AF: 0.0547 AC: 203

ALSPAC AF: 0.0571 AC: 220

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.0513 AC: 441

ExAC AF: 0.0487 AC: 5909

Asia WGS AF: 0.0520 AC: 179 AN: 3478

EpiCase AF: 0.0530

EpiControl AF: 0.0549

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.17
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.23
MPC		0.46
ClinPred		0.016	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.76
gMVP		0.73
Mutation Taster		=93/7	polymorphism (auto)

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: rs1801690; hg19: chr17-64208285; COSMIC: COSV52774426; COSMIC: COSV52774426;