rs192187532

Variant names:

• chr1-173909700-C-T
• rs192187532
• NM_000488.4:c.1005G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2_Supporting

The NM_000488.4(SERPINC1):​c.1005G>A​(p.Val335Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,614,100 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene SERPINC1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: SERPINC1 NM_000488.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.453
• 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

Specifications for SERPINC1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-173909700-C-T is Benign according to our data. Variant chr1-173909700-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 293838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.453 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00044 (67/152358) while in subpopulation EAS AF = 0.0118 (61/5190). AF 95% confidence interval is 0.00939. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1005G>A	p.Val335Val	synonymous	Exon 5 of 7	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.1128G>A	p.Val376Val	synonymous	Exon 5 of 7	NP_001373231.1
	SERPINC1	NM_001386303.1		c.1086G>A	p.Val362Val	synonymous	Exon 6 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.1005G>A	p.Val335Val	synonymous	Exon 5 of 7	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.1134G>A	p.Val378Val	synonymous	Exon 5 of 7	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.1128G>A	p.Val376Val	synonymous	Exon 5 of 7	ENSP00000544383.1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0117

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00103 AC: 258 AN: 251370 AF XY: 0.000950

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000262 AC: 383 AN: 1461742 Hom.: 3 Cov.: 48 AF XY: 0.000239 AC XY: 174 AN XY: 727174

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00756 AC: 300 AN: 39670

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111930

Other (OTH) AF: 0.00106 AC: 64 AN: 60382

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0118 AC: 61 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.0000818 Hom.: 0

Bravo AF: 0.000446

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary antithrombin deficiency (3)
-	-	1	SERPINC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.63
PhyloP100		0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs192187532; hg19: chr1-173878838;