rs574547491

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBP6_Very_Strong

The NM_000488.4(SERPINC1):c.553A>G(p.Thr185Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000898 in 1,614,160 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000095 ( 2 hom. )

Consequence

SERPINC1
NM_000488.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel B:2

Conservation

PhyloP100: -0.0950

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]

SERPINC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000488.4

BP4

Computational evidence support a benign effect (MetaRNN=0.01093325).

BP6

Variant 1-173911870-T-C is Benign according to our data. Variant chr1-173911870-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 529742.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINC1	NM_000488.4 linkuse as main transcript	c.553A>G	p.Thr185Ala	missense_variant	3/7	ENST00000367698.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINC1	ENST00000367698.4 linkuse as main transcript	c.553A>G	p.Thr185Ala	missense_variant	3/7	1	NM_000488.4	P1
SERPINC1	ENST00000487183.1 linkuse as main transcript	n.258A>G		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000219

AC:

AN:

251482

Hom.:

AF XY:

0.000331

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00180

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000951

AC:

139

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

110

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00159

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000492

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.000222

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary antithrombin deficiency

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	- -
Likely benign, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Jul 25, 2023	The c.553A>G (NM_000488.3) variant in SERPINC1 is a missense variant predicted to cause substitution of threonine by alanine at amino acid 185 (p.Thr185Ala). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001796 (55/30616 alleles) in the South Asian population, which is higher than the ClinGen SERPINC1 threshold ([>0.0002]) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.168, which is below the threshold of 0.3, and the splice site predictors VarSEAK and Splice AI indicated that the variant has no impact on splicing, which suggests that the variant does not impact SERPINC1 function (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BS1, BS4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.46

Cadd

Benign

7.5

Dann

Benign

0.50

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.11

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.92

MutationTaster

Benign

0.98

PrimateAI

Benign

0.38

Sift4G

Benign

0.29

T;T

Polyphen

0.0

.;B

Vest4

0.11

MutPred

0.26

Loss of phosphorylation at T185 (P = 0.0853);Loss of phosphorylation at T185 (P = 0.0853);

MVP

0.42

MPC

0.35

ClinPred

0.016

GERP RS

3.3

Varity_R

0.19

gMVP

0.45

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over