rs5877

Variant names:

• chr1-173909724-T-C
• rs5877
• NM_000488.4:c.981A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-173909724-T-C
• chr1-173909724-T-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BA1 BP4 BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.981A>G (p.Val327=) variant is reported at an Popmax FAF MAF of 0.7471 (19267/24962 alleles) in the African/African-American population in the genomes in gnomAD v2.1.1 with a total of 26873 homozygotes, meeting BA1 criteria of FAF >= 0.002. The variant has been reported in one heterozygous individual with normal AT activity levels (85%) meeting BS2_Supporting criteria. This synonymous variant is not predicted to impact splicing by SpliceAI and VARSEAK meeting BP4 criteria. 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, BP4, BS2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1251300/MONDO:0013144/084

• Frequency:
  • Genomes: 𝑓 0.48 (20230 hom., cov: 33)
  • Exomes 𝑓: 0.36 (100463 hom.)
• Consequence: SERPINC1 NM_000488.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 2.06
• Publications: 43 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

Specifications for SERPINC1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: 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.981A>G	p.Val327Val	synonymous	Exon 5 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.1104A>G	p.Val368Val	synonymous	Exon 5 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.1062A>G	p.Val354Val	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.981A>G	p.Val327Val	synonymous	Exon 5 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.1110A>G	p.Val370Val	synonymous	Exon 5 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.1104A>G	p.Val368Val	synonymous	Exon 5 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72443 AN: 152088 Hom.: 20178 Cov.: 33

Gnomad AFR AF: 0.766

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.467

GnomAD2 exomes AF: 0.402 AC: 100924 AN: 251348 AF XY: 0.396

Gnomad AFR exome AF: 0.777

Gnomad AMR exome AF: 0.336

Gnomad ASJ exome AF: 0.534

Gnomad EAS exome AF: 0.671

Gnomad FIN exome AF: 0.283

Gnomad NFE exome AF: 0.341

Gnomad OTH exome AF: 0.400

GnomAD4 exome AF: 0.359 AC: 525175 AN: 1461580 Hom.: 100463 Cov.: 47 AF XY: 0.359 AC XY: 261338 AN XY: 727080

African (AFR) AF: 0.785 AC: 26275 AN: 33480

American (AMR) AF: 0.343 AC: 15318 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.536 AC: 14002 AN: 26132

East Asian (EAS) AF: 0.618 AC: 24552 AN: 39700

South Asian (SAS) AF: 0.383 AC: 33036 AN: 86248

European-Finnish (FIN) AF: 0.287 AC: 15323 AN: 53414

Middle Eastern (MID) AF: 0.490 AC: 2827 AN: 5766

European-Non Finnish (NFE) AF: 0.332 AC: 369383 AN: 1111734

Other (OTH) AF: 0.405 AC: 24459 AN: 60382

GnomAD4 genome AF: 0.477 AC: 72557 AN: 152206 Hom.: 20230 Cov.: 33 AF XY: 0.472 AC XY: 35129 AN XY: 74426

African (AFR) AF: 0.766 AC: 31822 AN: 41540

American (AMR) AF: 0.414 AC: 6332 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1871 AN: 3470

East Asian (EAS) AF: 0.642 AC: 3328 AN: 5180

South Asian (SAS) AF: 0.385 AC: 1858 AN: 4824

European-Finnish (FIN) AF: 0.279 AC: 2959 AN: 10598

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 22948 AN: 67986

Other (OTH) AF: 0.467 AC: 989 AN: 2116

Alfa AF: 0.398 Hom.: 23493

Bravo AF: 0.501

Asia WGS AF: 0.523 AC: 1819 AN: 3478

EpiCase AF: 0.363

EpiControl AF: 0.363

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.2
DANN	Benign	0.48
PhyloP100		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs5877; hg19: chr1-173878862; COSMIC: COSV62929421; COSMIC: COSV62929421;