chr17-66226124-G-A

Variant names:

• chr17-66226124-G-A
• rs373786395
• NM_000042.3:c.242C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000042.3(APOH):​c.242C>T​(p.Pro81Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,450,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: APOH NM_000042.3 missense, splice_region
• Scores: Splicing: ADA: 0.06253
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.36

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOH	NM_000042.3	c.242C>T	p.Pro81Leu	missense_variant, splice_region_variant	Exon 3 of 8	ENST00000205948.11	NP_000033.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOH	ENST00000205948.11	c.242C>T	p.Pro81Leu	missense_variant, splice_region_variant	Exon 3 of 8	1	NM_000042.3	ENSP00000205948.6
APOH	ENST00000581797.5	c.62C>T	p.Pro21Leu	missense_variant, splice_region_variant	Exon 3 of 6	3		ENSP00000463553.1
APOH	ENST00000577982.1	c.242C>T	p.Pro81Leu	missense_variant, splice_region_variant	Exon 4 of 6	5		ENSP00000464301.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000410 AC: 1 AN: 244028 Hom.: 0 AF XY: 0.00000760 AC XY: 1 AN XY: 131636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450242 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 720882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Benign	0.95
DEOGEN2	Uncertain	0.60	D;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.3	D;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0050	D;.;.
Sift4G	Uncertain	0.019	D;.;.
Polyphen		1.0	D;.;.
Vest4		0.64
MutPred		0.54		Loss of methylation at K78 (P = 0.0445);.;Loss of methylation at K78 (P = 0.0445);
MVP		0.89
MPC		0.66
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.66
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.063
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.040		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: rs373786395; hg19: chr17-64222242;