rs2759328

Variant names:

• chr1-173907567-C-T
• rs2759328
• NM_000488.4:c.1154-53G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-173907567-C-T
• chr1-173907567-C-A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BS2 BA1

This summary comes from the ClinGen Evidence Repository: The NM_000488.4:c.1154-53G>A variant is reported at a popmax FAF of 0.3028 and the highest MAF of 0.3263 (32%; 507/1554 alleles with 81 homozygotes) in the East Asian population in gnomAD v2.1.1, meeting criteria for BA1 (MAF >0.002). The variant is reported in 8 individuals with normal antithrombin levels. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BA1, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10960823/MONDO:0013144/084

• Frequency:
  • Genomes: 𝑓 0.10 (950 hom., cov: 31)
  • Exomes 𝑓: 0.11 (8402 hom.)
• Consequence: SERPINC1 NM_000488.4 intron
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 0.0860
• Publications: 11 publications found

Genes affected

SERPINC1 (HGNC:775): (serpin family C member 1) The protein encoded by this gene, antithrombin III, is a plasma protease inhibitor and a member of the serpin superfamily. This protein inhibits thrombin as well as other activated serine proteases of the coagulation system, and it regulates the blood coagulation cascade. The protein includes two functional domains: the heparin binding-domain at the N-terminus of the mature protein, and the reactive site domain at the C-terminus. The inhibitory activity is enhanced by the presence of heparin. Numerous mutations have been identified for this gene, many of which are known to cause antithrombin-III deficiency which constitutes a strong risk factor for thrombosis. A reduction in the serum level of this protein is associated with severe cases of Coronavirus Disease 19 (COVID-19). [provided by RefSeq, Sep 2020]

SERPINC1 Gene-Disease associations (from GenCC):

• hereditary antithrombin deficiency

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000488.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINC1	NM_000488.4	MANE Select	c.1154-53G>A		intron	N/A	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.1277-53G>A		intron	N/A	NP_001373231.1
	SERPINC1	NM_001386303.1		c.1235-53G>A		intron	N/A	NP_001373232.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINC1	ENST00000367698.4	TSL:1 MANE Select	c.1154-53G>A		intron	N/A	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.1283-53G>A		intron	N/A	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.1277-53G>A		intron	N/A	ENSP00000544383.1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15213 AN: 152108 Hom.: 950 Cov.: 31

Gnomad AFR AF: 0.0643

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.0870

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.115 AC: 133561 AN: 1161880 Hom.: 8402 AF XY: 0.116 AC XY: 68918 AN XY: 592314

African (AFR) AF: 0.0638 AC: 1751 AN: 27464

American (AMR) AF: 0.0522 AC: 2315 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 3711 AN: 24410

East Asian (EAS) AF: 0.283 AC: 10884 AN: 38438

South Asian (SAS) AF: 0.149 AC: 11981 AN: 80402

European-Finnish (FIN) AF: 0.102 AC: 5430 AN: 53264

Middle Eastern (MID) AF: 0.0968 AC: 504 AN: 5208

European-Non Finnish (NFE) AF: 0.108 AC: 90641 AN: 837806

Other (OTH) AF: 0.126 AC: 6344 AN: 50546

GnomAD4 genome AF: 0.100 AC: 15219 AN: 152226 Hom.: 950 Cov.: 31 AF XY: 0.102 AC XY: 7585 AN XY: 74420

African (AFR) AF: 0.0642 AC: 2668 AN: 41544

American (AMR) AF: 0.0869 AC: 1329 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3470

East Asian (EAS) AF: 0.309 AC: 1597 AN: 5176

South Asian (SAS) AF: 0.141 AC: 679 AN: 4816

European-Finnish (FIN) AF: 0.106 AC: 1123 AN: 10590

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6914 AN: 68022

Other (OTH) AF: 0.113 AC: 238 AN: 2112

Alfa AF: 0.0895 Hom.: 149

Bravo AF: 0.0967

Asia WGS AF: 0.225 AC: 779 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary antithrombin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.0
DANN	Benign	0.59
PhyloP100		0.086
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2759328; hg19: chr1-173876705; COSMIC: COSV62929491; COSMIC: COSV62929491;