17-66216941-G-A

Variant names:

• chr17-66216941-G-A
• NM_000042.3:c.631C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000042.3(APOH):​c.631C>T​(p.Pro211Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,450,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: APOH NM_000042.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOH	NM_000042.3	c.631C>T	p.Pro211Ser	missense_variant	Exon 6 of 8	ENST00000205948.11	NP_000033.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOH	ENST00000205948.11	c.631C>T	p.Pro211Ser	missense_variant	Exon 6 of 8	1	NM_000042.3	ENSP00000205948.6
APOH	ENST00000581797.5	c.451C>T	p.Pro151Ser	missense_variant	Exon 6 of 6	3		ENSP00000463553.1
APOH	ENST00000585162.1	c.103C>T	p.Pro35Ser	missense_variant	Exon 2 of 3	2		ENSP00000462260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450010 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 721024

African (AFR) AF: 0.00 AC: 0 AN: 32826

American (AMR) AF: 0.00 AC: 0 AN: 41864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25686

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107682

Other (OTH) AF: 0.00 AC: 0 AN: 59956

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.631C>T (p.P211S) alteration is located in exon 6 (coding exon 6) of the APOH gene. This alteration results from a C to T substitution at nucleotide position 631, causing the proline (P) at amino acid position 211 to be replaced by a serine (S). 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	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Benign	0.39	T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.8	M;.
PhyloP100		4.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Uncertain	0.41
Sift	Benign	0.32	T;.
Sift4G	Benign	0.52	T;.
Polyphen		0.94	P;.
Vest4		0.52
MutPred		0.62		Gain of sheet (P = 0.0827);.;
MVP		0.77
MPC		0.63
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.60
gMVP		0.81

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

Other links and lift over

hg19: chr17-64213059;