rs121909548

chr1-173904038-C-Achr1-173904038-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000488.4(SERPINC1):c.1246G>T(p.Ala416Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,228 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A416P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (1 hom.)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2 B:2
• Conservation: PhyloP100: 7.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000488.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-173904038-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2164593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINC1	NM_000488.4	c.1246G>T	p.Ala416Ser	missense_variant	7/7	ENST00000367698.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINC1	ENST00000367698.4	c.1246G>T	p.Ala416Ser	missense_variant	7/7	1	NM_000488.4	P1

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000887 AC: 223 AN: 251358 Hom.: 0 AF XY: 0.000832 AC XY: 113 AN XY: 135860

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00149 AC: 2185 AN: 1461878 Hom.: 1 Cov.: 31 AF XY: 0.00139 AC XY: 1009 AN XY: 727242

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00181

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.000899 AC XY: 67 AN XY: 74506

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.00120

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000717 AC: 87

EpiCase AF: 0.00169

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:3 Uncertain:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 22, 1991	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely pathogenic, no assertion criteria provided	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 28, 2021	ACMG classification criteria: PS3 supporting, PS4 strong, PM3 moderate -
Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2022	PP1_strong, PS3, PS4 -

Thrombocytopenia;C1458140:Abnormal bleeding Uncertain:1

Uncertain significance, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Pathogenic	0.24
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	0.37	D
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.019	D;D
Polyphen		1.0	.;D
Vest4		0.59
MVP		0.86
MPC		1.1
ClinPred		0.15	T
GERP RS		5.7
Varity_R		0.85
gMVP		0.84

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

Other links and lift over

dbSNP: rs121909548; hg19: chr1-173873176;