rs143521873

Variant summary

Our verdict is Uncertain significance. Variant got -3 ACMG points: 1P and 4B. BS1PP3

This summary comes from the ClinGen Evidence Repository: The c.529C>T (p.Arg177Cys) variant is reported at a POPMAX FAF of 0.001545 in the African/African American population in gnomAD v3.1.2, and is >BS1 cut-off of 0.0002. One proband in PMID:28300866 and three probands from internal data with AT deficiency are noted to carry the variant ; however PS4 is not applied since BS1 is met. The variant has a REVEL score of 0.873, which exceeds the cutoff (>0.6) set by the VCEP. Thrombosis VCEP considers this variant as a variant of uncertain significance due to the presence of at least 4 cases with AT deficiency and a high REVEL score. While the population frequency is high, the absence of homozygotes in the population may argue against the variant being benign. The experimental evidence is unreliable with varying activity levels on different assays. A conservative approach would be to classify this variant as uncertain. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1251403/MONDO:0013144/084

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

SERPINC1
NM_000488.4 missense

Scores

11
6
2

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:1

Conservation

PhyloP100: 9.60
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -3 ACMG points.

PP3
For more information check the summary or visit ClinGen Evidence Repository.
BS1
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.529C>T p.Arg177Cys missense_variant 3/7 ENST00000367698.4 NP_000479.1 P01008A0A024R944

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SERPINC1ENST00000367698.4 linkuse as main transcriptc.529C>T p.Arg177Cys missense_variant 3/71 NM_000488.4 ENSP00000356671.3 P01008
SERPINC1ENST00000487183.1 linkuse as main transcriptn.234C>T non_coding_transcript_exon_variant 2/42

Frequencies

GnomAD3 genomes
AF:
0.000539
AC:
82
AN:
152196
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00188
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000123
AC:
31
AN:
251482
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.00166
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000588
AC:
86
AN:
1461864
Hom.:
0
Cov.:
32
AF XY:
0.0000440
AC XY:
32
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.00170
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.000539
AC:
82
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.000538
AC XY:
40
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00188
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000143
Hom.:
0
Bravo
AF:
0.000518
ESP6500AA
AF:
0.00227
AC:
10
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2Benign:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hereditary antithrombin deficiency Uncertain:1Benign:1
Uncertain significance, reviewed by expert panelcurationClingen Thrombosis Variant Curation Expert Panel, ClinGenSep 21, 2023The c.529C>T (p.Arg177Cys) variant is reported at a POPMAX FAF of 0.001545 in the African/African American population in gnomAD v3.1.2, and is >BS1 cut-off of 0.0002. One proband in PMID: 28300866 and three probands from internal data with AT deficiency are noted to carry the variant ; however PS4 is not applied since BS1 is met. The variant has a REVEL score of 0.873, which exceeds the cutoff (>0.6) set by the VCEP. Thrombosis VCEP considers this variant as a variant of uncertain significance due to the presence of at least 4 cases with AT deficiency and a high REVEL score. While the population frequency is high, the absence of homozygotes in the population may argue against the variant being benign. The experimental evidence is unreliable with varying activity levels on different assays. A conservative approach would be to classify this variant as uncertain. In summary, based on the evidence available at this time, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, PP3. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 03, 2024- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterAug 02, 2023PP3 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.89
.;D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Uncertain
0.72
D;D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Pathogenic
3.8
.;H
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-6.6
.;D
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
.;D
Sift4G
Uncertain
0.011
D;D
Polyphen
1.0
.;D
Vest4
0.91
MVP
0.92
MPC
1.3
ClinPred
0.47
T
GERP RS
5.7
Varity_R
0.76
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs143521873; hg19: chr1-173881032; COSMIC: COSV104424404; COSMIC: COSV104424404; API