1-173912755-C-T

Variant names:

• chr1-173912755-C-T
• rs941988
• NM_000488.4:c.409-741G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000488.4(SERPINC1):​c.409-741G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0998 in 152,066 control chromosomes in the GnomAD database, including 937 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene SERPINC1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.10 (937 hom., cov: 32)
• Consequence: SERPINC1 NM_000488.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.167
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 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.409-741G>A		intron	N/A	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.409-741G>A		intron	N/A	NP_001373231.1
	SERPINC1	NM_001386303.1		c.490-741G>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.409-741G>A		intron	N/A	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.409-741G>A		intron	N/A	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.409-741G>A		intron	N/A	ENSP00000544383.1

Frequencies

GnomAD3 genomes AF: 0.0998 AC: 15165 AN: 151948 Hom.: 937 Cov.: 32

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0866

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.112

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0998 AC: 15172 AN: 152066 Hom.: 937 Cov.: 32 AF XY: 0.102 AC XY: 7569 AN XY: 74332

African (AFR) AF: 0.0640 AC: 2657 AN: 41506

American (AMR) AF: 0.0865 AC: 1321 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3472

East Asian (EAS) AF: 0.308 AC: 1594 AN: 5168

South Asian (SAS) AF: 0.141 AC: 680 AN: 4818

European-Finnish (FIN) AF: 0.105 AC: 1105 AN: 10568

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

European-Non Finnish (NFE) AF: 0.102 AC: 6902 AN: 67948

Other (OTH) AF: 0.114 AC: 240 AN: 2104

Alfa AF: 0.0948 Hom.: 157

Bravo AF: 0.0966

Asia WGS AF: 0.220 AC: 764 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.9
DANN	Benign	0.41
PhyloP100		-0.17
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: rs941988; hg19: chr1-173881893;