rs2227589

Variant names:

• chr1-173917078-C-T
• rs2227589
• NM_000488.4:c.41+141G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-173917078-C-T
• chr1-173917078-C-A
• chr1-173917078-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000488.4(SERPINC1):​c.41+141G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 754,080 control chromosomes in the GnomAD database, including 5,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (956 hom., cov: 32)
  • Exomes 𝑓: 0.12 (4798 hom.)
• Consequence: SERPINC1 NM_000488.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.894
• Publications: 46 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

ENSG00000305649 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-173917078-C-T is Benign according to our data. Variant chr1-173917078-C-T is described in ClinVar as Benign. ClinVar VariationId is 1287399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

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.41+141G>A		intron	N/A	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.41+141G>A		intron	N/A	NP_001373231.1
	SERPINC1	NM_001386303.1		c.24+158G>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.41+141G>A		intron	N/A	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.41+141G>A		intron	N/A	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.41+141G>A		intron	N/A	ENSP00000544383.1

Frequencies

GnomAD3 genomes AF: 0.0997 AC: 15164 AN: 152038 Hom.: 956 Cov.: 32

Gnomad AFR AF: 0.0637

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0861

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.115 AC: 69336 AN: 601924 Hom.: 4798 AF XY: 0.118 AC XY: 37737 AN XY: 321002

African (AFR) AF: 0.0607 AC: 1031 AN: 16988

American (AMR) AF: 0.0548 AC: 1820 AN: 33242

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 2838 AN: 18608

East Asian (EAS) AF: 0.276 AC: 9248 AN: 33496

South Asian (SAS) AF: 0.148 AC: 9006 AN: 60686

European-Finnish (FIN) AF: 0.100 AC: 4812 AN: 47908

Middle Eastern (MID) AF: 0.103 AC: 284 AN: 2754

European-Non Finnish (NFE) AF: 0.102 AC: 36427 AN: 356596

Other (OTH) AF: 0.122 AC: 3870 AN: 31646

GnomAD4 genome AF: 0.0997 AC: 15170 AN: 152156 Hom.: 956 Cov.: 32 AF XY: 0.102 AC XY: 7580 AN XY: 74398

African (AFR) AF: 0.0635 AC: 2639 AN: 41532

American (AMR) AF: 0.0860 AC: 1313 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 559 AN: 3472

East Asian (EAS) AF: 0.309 AC: 1597 AN: 5164

South Asian (SAS) AF: 0.142 AC: 685 AN: 4830

European-Finnish (FIN) AF: 0.105 AC: 1118 AN: 10598

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

European-Non Finnish (NFE) AF: 0.101 AC: 6893 AN: 67974

Other (OTH) AF: 0.114 AC: 240 AN: 2108

Alfa AF: 0.0947 Hom.: 1110

Bravo AF: 0.0966

Asia WGS AF: 0.222 AC: 770 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.4
DANN	Benign	0.76
PhyloP100		-0.89
PromoterAI		-0.12	Neutral
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: rs2227589; hg19: chr1-173886216; COSMIC: COSV62929275; COSMIC: COSV62929275;