17-66228037-T-C

Position:

• chr17-66228037-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000205948.11(APOH):​c.224A>G​(p.Asn75Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,613,890 control chromosomes in the GnomAD database, including 219 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (196 hom.)
• Consequence: APOH ENST00000205948.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.11

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026151836).
• BP6: Variant 17-66228037-T-C is Benign according to our data. Variant chr17-66228037-T-C is described in ClinVar as [Benign]. Clinvar id is 771498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOH	NM_000042.3	c.224A>G	p.Asn75Ser	missense_variant	2/8	ENST00000205948.11	NP_000033.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOH	ENST00000205948.11	c.224A>G	p.Asn75Ser	missense_variant	2/8	1	NM_000042.3	ENSP00000205948	P1
APOH	ENST00000581797.5	c.44A>G	p.Asn15Ser	missense_variant	2/6	3		ENSP00000463553
APOH	ENST00000577982.1	c.224A>G	p.Asn75Ser	missense_variant	3/6	5		ENSP00000464301

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 697 AN: 152174 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0124 AC: 3123 AN: 250994 Hom.: 172 AF XY: 0.00944 AC XY: 1281 AN XY: 135658

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0885

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00268 AC: 3923 AN: 1461598 Hom.: 196 Cov.: 31 AF XY: 0.00227 AC XY: 1650 AN XY: 727112

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0823

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00462 AC: 704 AN: 152292 Hom.: 23 Cov.: 32 AF XY: 0.00526 AC XY: 392 AN XY: 74484

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.0427

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000700 Hom.: 3

Bravo AF: 0.00819

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00961 AC: 1167

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.23	T;.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.84	T;D;D
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N;.;.
REVEL	Benign	0.10
Sift	Benign	0.62	T;.;.
Sift4G	Benign	0.66	T;.;.
Polyphen		0.57	P;.;.
Vest4		0.59
MPC		0.17
ClinPred		0.025	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138225887; hg19: chr17-64224155;