1-173904013-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3PM1PM2_SupportingPS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1271G>A variant in SERPINC1 is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 424 (p.Gly424Asp). This variant has been reported in one family meeting an antithrombin activity level of < 0.8 IU/mL and a family history of reported abnormal antithrombin levels (PS4_Supporting; PMID:1547341).The computational predictor REVEL gives a score of 0.635, which is above the threshold of 0.6, evidence that correlates with impact to SERPINC1 function (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting).In summary, this variant meets the criteria to be classified as uncertain significance due to insufficient evidence for autosomal dominant hereditary antithrombin deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Thrombosis VCEP: PP3, PM2_Supporting, PS4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA210785/MONDO:0013144/084

Frequency

Genomes: not found (cov: 32)

Consequence

SERPINC1
ENST00000367698.4 missense

Scores

5
11
3

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.42
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SERPINC1NM_000488.4 linkuse as main transcriptc.1271G>A p.Gly424Asp missense_variant 7/7 ENST00000367698.4 NP_000479.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SERPINC1ENST00000367698.4 linkuse as main transcriptc.1271G>A p.Gly424Asp missense_variant 7/71 NM_000488.4 ENSP00000356671 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 1992- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.77
.;D
Eigen
Uncertain
0.68
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Uncertain
-0.0032
T
MutationAssessor
Uncertain
2.3
.;M
MutationTaster
Benign
1.0
A
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-2.8
.;D
REVEL
Uncertain
0.64
Sift
Benign
0.21
.;T
Sift4G
Benign
0.49
T;T
Polyphen
1.0
.;D
Vest4
0.97
MutPred
0.51
.;Loss of methylation at R425 (P = 0.0449);
MVP
0.86
MPC
1.3
ClinPred
0.99
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.83
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121909566; hg19: chr1-173873151; API