rs121909555

Variant names:

• chr1-173903968-G-A
• rs121909555
• NM_000488.4:c.1316C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-173903968-G-A
• chr1-173903968-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4_Supporting PM2_Supporting PP3 PP1_Moderate PM5

This summary comes from the ClinGen Evidence Repository: The c.1316C>T (NM_000488.4) variant in SERPINC1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 439 (p.Pro439Leu). This variant has been reported in one proband meeting the phenotypic criteria of an antithrombin activity level of < 0.8 IU/mL and a positive family history. (PS4_Supporting; PMIDs: 6877092, 3191114). 12 segregations are counted in the Utah family where 13 members are identified as AT-deficient. 11 individuals showed electrophoretically abnormal AT; 2 individuals are obligate carriers. PMID:3191114 performed sequence analysis on this family. Based on RFLP analysis in this paper, 12 segregations may be counted. However, criteria for PP1_Strong is not met as segregations across >1 family is required (PP1_Moderate; PMID:2983542, 3191114). This variant is absent from gnomAD v2.1.1 and v3.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.952, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). Another missense variant c.1315C>A (p.Pro439Thr) (ClinVarID:627228) in the same codon has been classified as pathogenic for autosomal dominant antithrombin III deficiency by the ClinGen Thrombosis VCEP (PM5).In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant antithrombin III deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP1, PM5, PP3, PM2, PS4. (ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0; date of approval) LINK:https://erepo.genome.network/evrepo/ui/classification/CA210764/MONDO:0013144/084

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.14
• Publications: 2 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.1316C>T	p.Pro439Leu	missense	Exon 7 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.1439C>T	p.Pro480Leu	missense	Exon 7 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.1397C>T	p.Pro466Leu	missense	Exon 8 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.1316C>T	p.Pro439Leu	missense	Exon 7 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.1445C>T	p.Pro482Leu	missense	Exon 7 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.1439C>T	p.Pro480Leu	missense	Exon 7 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary antithrombin deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		9.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-9.1	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.96		Gain of MoRF binding (P = 0.0506)
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.98
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs121909555; hg19: chr1-173873106;