1-173911870-T-A

Variant names:

• chr1-173911870-T-A
• rs574547491
• NM_000488.4:c.553A>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM1 PP2 BP4_Strong

The NM_000488.4(SERPINC1):​c.553A>T​(p.Thr185Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T185A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SERPINC1 NM_000488.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0950
• Publications: 0 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

Our verdict: Likely_benign. The variant received -1 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, 8 uncertain in NM_000488.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 1.3587 (below the threshold of 3.09). Trascript score misZ: 2.7609 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary antithrombin deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0661563).

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.553A>T	p.Thr185Ser	missense	Exon 3 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.553A>T	p.Thr185Ser	missense	Exon 3 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.634A>T	p.Thr212Ser	missense	Exon 4 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.553A>T	p.Thr185Ser	missense	Exon 3 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.553A>T	p.Thr185Ser	missense	Exon 3 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.553A>T	p.Thr185Ser	missense	Exon 3 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111998

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.3
DANN	Benign	0.62
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.10	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.095
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.16
Sift	Benign	0.38	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.28		Gain of disorder (P = 0.0585)
MVP		0.35
MPC		0.32
ClinPred		0.058	T
GERP RS		3.3
Varity_R		0.22
gMVP		0.36
Mutation Taster		=83/17	polymorphism

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: rs574547491; hg19: chr1-173881008;