chr17-66220736-A-G

Position:

• chr17-66220736-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000042.3(APOH):​c.422T>C​(p.Ile141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0656 in 1,602,108 control chromosomes in the GnomAD database, including 3,692 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.073 (426 hom., cov: 31)
  • Exomes 𝑓: 0.065 (3266 hom.)
• Consequence: APOH NM_000042.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.32

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031048357).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOH	NM_000042.3	c.422T>C	p.Ile141Thr	missense_variant	5/8	ENST00000205948.11	NP_000033.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOH	ENST00000205948.11	c.422T>C	p.Ile141Thr	missense_variant	5/8	1	NM_000042.3	ENSP00000205948.6
APOH	ENST00000581797.5	c.242T>C	p.Ile81Thr	missense_variant	5/6	3		ENSP00000463553.1
APOH	ENST00000577982.1	c.422T>C	p.Ile141Thr	missense_variant	6/6	5		ENSP00000464301.1

Frequencies

GnomAD3 genomes AF: 0.0730 AC: 11109 AN: 152090 Hom.: 423 Cov.: 31

Gnomad AFR AF: 0.0978

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0466

Gnomad ASJ AF: 0.0714

Gnomad EAS AF: 0.0642

Gnomad SAS AF: 0.0532

Gnomad FIN AF: 0.0890

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0641

Gnomad OTH AF: 0.0703

GnomAD3 exomes AF: 0.0644 AC: 16061 AN: 249456 Hom.: 610 AF XY: 0.0639 AC XY: 8606 AN XY: 134748

Gnomad AFR exome AF: 0.0986

Gnomad AMR exome AF: 0.0300

Gnomad ASJ exome AF: 0.0674

Gnomad EAS exome AF: 0.0616

Gnomad SAS exome AF: 0.0515

Gnomad FIN exome AF: 0.0971

Gnomad NFE exome AF: 0.0671

Gnomad OTH exome AF: 0.0671

GnomAD4 exome AF: 0.0649 AC: 94052 AN: 1449900 Hom.: 3266 Cov.: 32 AF XY: 0.0650 AC XY: 46767 AN XY: 719726

Gnomad4 AFR exome AF: 0.0949

Gnomad4 AMR exome AF: 0.0311

Gnomad4 ASJ exome AF: 0.0697

Gnomad4 EAS exome AF: 0.0714

Gnomad4 SAS exome AF: 0.0499

Gnomad4 FIN exome AF: 0.0948

Gnomad4 NFE exome AF: 0.0649

Gnomad4 OTH exome AF: 0.0611

GnomAD4 genome AF: 0.0731 AC: 11123 AN: 152208 Hom.: 426 Cov.: 31 AF XY: 0.0724 AC XY: 5390 AN XY: 74408

Gnomad4 AFR AF: 0.0979

Gnomad4 AMR AF: 0.0466

Gnomad4 ASJ AF: 0.0714

Gnomad4 EAS AF: 0.0639

Gnomad4 SAS AF: 0.0533

Gnomad4 FIN AF: 0.0890

Gnomad4 NFE AF: 0.0642

Gnomad4 OTH AF: 0.0701

Alfa AF: 0.0658 Hom.: 445

Bravo AF: 0.0702

TwinsUK AF: 0.0642 AC: 238

ALSPAC AF: 0.0693 AC: 267

ESP6500AA AF: 0.0901 AC: 397

ESP6500EA AF: 0.0651 AC: 560

ExAC AF: 0.0658 AC: 7984

Asia WGS AF: 0.0600 AC: 209 AN: 3478

EpiCase AF: 0.0643

EpiControl AF: 0.0686

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.59
DEOGEN2	Benign	0.091	T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.18	T;T;T
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.9	N;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	2.7	N;.;.
REVEL	Benign	0.065
Sift	Benign	1.0	T;.;.
Sift4G	Benign	1.0	T;.;.
Polyphen		0.0	B;.;.
Vest4		0.053
MPC		0.20
ClinPred		0.0043	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.42

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: rs52797880; hg19: chr17-64216854; COSMIC: COSV52771870; COSMIC: COSV52771870;