17-66220681-T-C

Variant names:

• chr17-66220681-T-C
• rs8178925
• NM_000042.3:c.477A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_000042.3(APOH):​c.477A>G​(p.Ser159Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00043 in 1,614,158 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: APOH NM_000042.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.887
• Publications: 1 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-66220681-T-C is Benign according to our data. Variant chr17-66220681-T-C is described in ClinVar as [Benign]. Clinvar id is 781328.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.887 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOH	NM_000042.3	c.477A>G	p.Ser159Ser	synonymous_variant	Exon 5 of 8	ENST00000205948.11	NP_000033.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOH	ENST00000205948.11	c.477A>G	p.Ser159Ser	synonymous_variant	Exon 5 of 8	1	NM_000042.3	ENSP00000205948.6
APOH	ENST00000581797.5	c.297A>G	p.Ser99Ser	synonymous_variant	Exon 5 of 6	3		ENSP00000463553.1
APOH	ENST00000577982.1	c.477A>G	p.Ser159Ser	synonymous_variant	Exon 6 of 6	5		ENSP00000464301.1
APOH	ENST00000585162.1	c.-52A>G		upstream_gene_variant		2		ENSP00000462260.1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 385 AN: 152160 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00908

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000625 AC: 157 AN: 251388 AF XY: 0.000324

Gnomad AFR exome AF: 0.00904

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000210 AC: 307 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.000171 AC XY: 124 AN XY: 727240

African (AFR) AF: 0.00809 AC: 271 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112004

Other (OTH) AF: 0.000348 AC: 21 AN: 60396

GnomAD4 genome AF: 0.00254 AC: 387 AN: 152278 Hom.: 3 Cov.: 31 AF XY: 0.00246 AC XY: 183 AN XY: 74454

African (AFR) AF: 0.00910 AC: 378 AN: 41552

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00198 Hom.: 1

Bravo AF: 0.00290

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.5
DANN	Benign	0.57
PhyloP100		-0.89
PromoterAI		-0.0023	Neutral
Mutation Taster		=100/0	polymorphism

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: rs8178925; hg19: chr17-64216799;