chr1-173909694-T-C

Variant names:

• chr1-173909694-T-C
• rs5878
• NM_000488.4:c.1011A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BA1 BP4 BS2_Supporting BP7

This summary comes from the ClinGen Evidence Repository: The variant is reported at a popmax FAF of 0.7651 and the highest MAF of 0.7792 (78%; 19440/24948 alleles with 7592 homozygotes) in the African/African-American population in gnomAD v2.1.1, meeting criteria for BA1 (MAF >0.002). The variant is reported in 1 individual with normal antithrombin levels. SpliceAI and VarSeak predict no impact on splicing and PhyloP gives a conservation score of 0.028 (<0.1). 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_Supporting, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1251296/MONDO:0013144/084

• Frequency:
  • Genomes: 𝑓 0.48 (20306 hom., cov: 33)
  • Exomes 𝑓: 0.36 (100658 hom.)
• Consequence: SERPINC1 NM_000488.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 0.121
• Publications: 38 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 -11 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• 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.1011A>G	p.Gln337Gln	synonymous	Exon 5 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.1134A>G	p.Gln378Gln	synonymous	Exon 5 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.1092A>G	p.Gln364Gln	synonymous	Exon 6 of 8	NP_001373232.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINC1	ENST00000367698.4	TSL:1 MANE Select	c.1011A>G	p.Gln337Gln	synonymous	Exon 5 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.1140A>G	p.Gln380Gln	synonymous	Exon 5 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.1134A>G	p.Gln378Gln	synonymous	Exon 5 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72441 AN: 152116 Hom.: 20255 Cov.: 33

Gnomad AFR AF: 0.772

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.464

GnomAD2 exomes AF: 0.394 AC: 99142 AN: 251340 AF XY: 0.391

Gnomad AFR exome AF: 0.785

Gnomad AMR exome AF: 0.274

Gnomad ASJ exome AF: 0.535

Gnomad EAS exome AF: 0.647

Gnomad FIN exome AF: 0.296

Gnomad NFE exome AF: 0.345

Gnomad OTH exome AF: 0.398

GnomAD4 exome AF: 0.360 AC: 526270 AN: 1461450 Hom.: 100658 Cov.: 51 AF XY: 0.360 AC XY: 262001 AN XY: 727022

African (AFR) AF: 0.792 AC: 26513 AN: 33478

American (AMR) AF: 0.282 AC: 12624 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 14011 AN: 26134

East Asian (EAS) AF: 0.577 AC: 22901 AN: 39686

South Asian (SAS) AF: 0.382 AC: 32981 AN: 86248

European-Finnish (FIN) AF: 0.300 AC: 15996 AN: 53402

Middle Eastern (MID) AF: 0.492 AC: 2838 AN: 5766

European-Non Finnish (NFE) AF: 0.336 AC: 373932 AN: 1111642

Other (OTH) AF: 0.405 AC: 24474 AN: 60372

GnomAD4 genome AF: 0.477 AC: 72555 AN: 152234 Hom.: 20306 Cov.: 33 AF XY: 0.472 AC XY: 35120 AN XY: 74434

African (AFR) AF: 0.773 AC: 32098 AN: 41540

American (AMR) AF: 0.378 AC: 5779 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1876 AN: 3468

East Asian (EAS) AF: 0.613 AC: 3179 AN: 5182

South Asian (SAS) AF: 0.384 AC: 1855 AN: 4826

European-Finnish (FIN) AF: 0.293 AC: 3110 AN: 10602

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23219 AN: 68004

Other (OTH) AF: 0.464 AC: 980 AN: 2110

Alfa AF: 0.397 Hom.: 21640

Bravo AF: 0.497

Asia WGS AF: 0.515 AC: 1793 AN: 3478

EpiCase AF: 0.367

EpiControl AF: 0.367

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary antithrombin deficiency (4)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.6
DANN	Benign	0.56
PhyloP100		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs5878; hg19: chr1-173878832; COSMIC: COSV62929416; COSMIC: COSV62929416;