1-173909333-A-G

Variant names:

• chr1-173909333-A-G
• rs1799876
• NM_000488.4:c.1153+219T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000488.4(SERPINC1):​c.1153+219T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 152,042 control chromosomes in the GnomAD database, including 19,290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.46 (19290 hom., cov: 32)
• Consequence: SERPINC1 NM_000488.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.51
• Publications: 13 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 1-173909333-A-G is Benign according to our data. Variant chr1-173909333-A-G is described in ClinVar as Benign. ClinVar VariationId is 1282645.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.756 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINC1	NM_000488.4	MANE Select	c.1153+219T>C		intron	N/A	NP_000479.1
	SERPINC1	NM_001386302.1		c.1276+219T>C		intron	N/A	NP_001373231.1
	SERPINC1	NM_001386303.1		c.1234+219T>C		intron	N/A	NP_001373232.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINC1	ENST00000367698.4	TSL:1 MANE Select	c.1153+219T>C		intron	N/A	ENSP00000356671.3

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70015 AN: 151924 Hom.: 19238 Cov.: 32

Gnomad AFR AF: 0.763

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.447

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

GnomAD4 genome AF: 0.461 AC: 70128 AN: 152042 Hom.: 19290 Cov.: 32 AF XY: 0.455 AC XY: 33800 AN XY: 74298

African (AFR) AF: 0.763 AC: 31654 AN: 41462

American (AMR) AF: 0.369 AC: 5641 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1788 AN: 3466

East Asian (EAS) AF: 0.619 AC: 3195 AN: 5160

South Asian (SAS) AF: 0.356 AC: 1714 AN: 4812

European-Finnish (FIN) AF: 0.251 AC: 2659 AN: 10574

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.325 AC: 22090 AN: 67980

Other (OTH) AF: 0.448 AC: 943 AN: 2104

Alfa AF: 0.391 Hom.: 4123

Bravo AF: 0.484

Asia WGS AF: 0.506 AC: 1761 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.10
DANN	Benign	0.58
PhyloP100		-1.5
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: rs1799876; hg19: chr1-173878471;