rs677

Positions:

• chr1-173907423-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4 BA1 BP7

This summary comes from the ClinGen Evidence Repository: The NM_000488.4:c.1218+27G>C variant is reported at an Popmax FAF MAF of 0.2409 (4979/19948 alleles) in the East Asian population in the genomes in gnomAD v2.1.1 with a total of 2550 homozygotes, meeting BA1 criteria of FAF >= 0.002. The variant is not predicted to cause a splicing impact by by SpliceAI and VARSEAK, and the nucleotide is not conserved with a PhyloP score of -1.65 and a PhastCons score of ~0. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BA1, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1251245/MONDO:0013144/084

• Frequency:
  • Genomes: 𝑓 0.096 (965 hom., cov: 31)
  • Exomes 𝑓: 0.12 (11170 hom.)
• Consequence: SERPINC1 NM_000488.4 intron
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: -1.64

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 Benign. Variant got -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINC1	NM_000488.4	c.1218+27G>C		intron_variant		ENST00000367698.4	NP_000479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINC1	ENST00000367698.4	c.1218+27G>C		intron_variant		1	NM_000488.4	ENSP00000356671.3

Frequencies

GnomAD3 genomes AF: 0.0963 AC: 14643 AN: 152024 Hom.: 967 Cov.: 31

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0930

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0988

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.106

GnomAD3 exomes AF: 0.125 AC: 31403 AN: 251440 Hom.: 2339 AF XY: 0.130 AC XY: 17684 AN XY: 135888

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.0773

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.249

Gnomad SAS exome AF: 0.159

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.120 AC: 170307 AN: 1415278 Hom.: 11170 Cov.: 24 AF XY: 0.123 AC XY: 86644 AN XY: 706802

Gnomad4 AFR exome AF: 0.0182

Gnomad4 AMR exome AF: 0.0772

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.233

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.0962 AC: 14640 AN: 152142 Hom.: 965 Cov.: 31 AF XY: 0.0964 AC XY: 7166 AN XY: 74374

Gnomad4 AFR AF: 0.0202

Gnomad4 AMR AF: 0.0929

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.242

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.0988

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.106

Alfa AF: 0.120 Hom.: 273

Bravo AF: 0.0915

Asia WGS AF: 0.160 AC: 556 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Hereditary antithrombin deficiency Benign:2

Benign, reviewed by expert panel	curation	Clingen Thrombosis Variant Curation Expert Panel, ClinGen	Jul 25, 2023	The NM_000488.4:c.1218+27G>C variant is reported at an Popmax FAF MAF of 0.2409 (4979/19948 alleles) in the East Asian population in the genomes in gnomAD v2.1.1 with a total of 2550 homozygotes, meeting BA1 criteria of FAF >= 0.002. The variant is not predicted to cause a splicing impact by by SpliceAI and VARSEAK, and the nucleotide is not conserved with a PhyloP score of -1.65 and a PhastCons score of ~0. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: BA1, BP4, BP7. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.018
DANN	Benign	0.50

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: rs677; hg19: chr1-173876561; COSMIC: COSV62929040; COSMIC: COSV62929040;