rs8178901

Variant names:

• chr17-66229308-G-A
• rs8178901
• NM_000042.3:c.64+8C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-66229308-G-A
• chr17-66229308-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000042.3(APOH):​c.64+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,611,992 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (50 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (39 hom.)
• Consequence: APOH NM_000042.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001726
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.480

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 17-66229308-G-A is Benign according to our data. Variant chr17-66229308-G-A is described in ClinVar as [Benign]. Clinvar id is 780449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0135 (2051/152310) while in subpopulation AFR AF = 0.0453 (1882/41560). AF 95% confidence interval is 0.0436. There are 50 homozygotes in GnomAd4. There are 917 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOH	NM_000042.3	c.64+8C>T		splice_region_variant, intron_variant	Intron 1 of 7	ENST00000205948.11	NP_000033.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOH	ENST00000205948.11	c.64+8C>T		splice_region_variant, intron_variant	Intron 1 of 7	1	NM_000042.3	ENSP00000205948.6
APOH	ENST00000577982.1	c.64+8C>T		splice_region_variant, intron_variant	Intron 2 of 5	5		ENSP00000464301.1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2050 AN: 152192 Hom.: 51 Cov.: 31

Gnomad AFR AF: 0.0454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00368 AC: 921 AN: 250036 AF XY: 0.00263

Gnomad AFR exome AF: 0.0480

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000204

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00147 AC: 2141 AN: 1459682 Hom.: 39 Cov.: 29 AF XY: 0.00128 AC XY: 933 AN XY: 726128

Gnomad4 AFR exome AF: 0.0465 AC: 1550 AN: 33356

Gnomad4 AMR exome AF: 0.00282 AC: 126 AN: 44660

Gnomad4 ASJ exome AF: 0.00253 AC: 66 AN: 26104

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39638

Gnomad4 SAS exome AF: 0.000209 AC: 18 AN: 86012

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53290

Gnomad4 NFE exome AF: 0.000143 AC: 159 AN: 1110562

Gnomad4 Remaining exome AF: 0.00320 AC: 193 AN: 60296

GnomAD4 genome AF: 0.0135 AC: 2051 AN: 152310 Hom.: 50 Cov.: 31 AF XY: 0.0123 AC XY: 917 AN XY: 74478

Gnomad4 AFR AF: 0.0453 AC: 0.0452839 AN: 0.0452839

Gnomad4 AMR AF: 0.00758 AC: 0.00758269 AN: 0.00758269

Gnomad4 ASJ AF: 0.00346 AC: 0.00345622 AN: 0.00345622

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000415 AC: 0.000414594 AN: 0.000414594

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000235 AC: 0.00023519 AN: 0.00023519

Gnomad4 OTH AF: 0.00945 AC: 0.0094518 AN: 0.0094518

Alfa AF: 0.00751 Hom.: 16

Bravo AF: 0.0164

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 12, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.0
DANN	Benign	0.81
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs8178901; hg19: chr17-64225426;