17-66220622-G-A

Variant names:

• chr17-66220622-G-A
• rs370127451
• NM_000042.3:c.536C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000042.3(APOH):​c.536C>T​(p.Ala179Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: APOH NM_000042.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31785882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOH	NM_000042.3	c.536C>T	p.Ala179Val	missense_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.536C>T	p.Ala179Val	missense_variant	Exon 5 of 8	1	NM_000042.3	ENSP00000205948.6
APOH	ENST00000581797.5	c.356C>T	p.Ala119Val	missense_variant	Exon 5 of 6	3		ENSP00000463553.1
APOH	ENST00000577982.1	c.536C>T	p.Ala179Val	missense_variant	Exon 6 of 6	5		ENSP00000464301.1
APOH	ENST00000585162.1	c.8C>T	p.Ala3Val	missense_variant	Exon 1 of 3	2		ENSP00000462260.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152064 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251462 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727232

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

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: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152180 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74388

African (AFR) AF: 0.0000723 AC: 3 AN: 41518

American (AMR) AF: 0.000393 AC: 6 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.536C>T (p.A179V) alteration is located in exon 5 (coding exon 5) of the APOH gene. This alteration results from a C to T substitution at nucleotide position 536, causing the alanine (A) at amino acid position 179 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.095	T;.;T
Eigen	Benign	-0.0075
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.3	L;.;.
PhyloP100		4.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N;.;.
REVEL	Benign	0.27
Sift	Benign	0.10	T;.;.
Sift4G	Benign	0.32	T;.;.
Polyphen		1.0	D;.;.
Vest4		0.37
MVP		0.48
MPC		0.28
ClinPred		0.20	T
GERP RS		4.4
PromoterAI		-0.023	Neutral
Varity_R		0.29
gMVP		0.50
Mutation Taster		=56/44	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: rs370127451; hg19: chr17-64216740;