chr1-173907423-C-G

Variant names:

• chr1-173907423-C-G
• rs677
• NM_000488.4:c.1218+27G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 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: Benign. The variant received -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.

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.1218+27G>C		intron	N/A	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.1341+27G>C		intron	N/A	NP_001373231.1
	SERPINC1	NM_001386303.1		c.1299+27G>C		intron	N/A	NP_001373232.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINC1	ENST00000367698.4	TSL:1 MANE Select	c.1218+27G>C		intron	N/A	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.1347+27G>C		intron	N/A	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.1341+27G>C		intron	N/A	ENSP00000544383.1

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

GnomAD2 exomes AF: 0.125 AC: 31403 AN: 251440 AF XY: 0.130

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 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

African (AFR) AF: 0.0182 AC: 592 AN: 32518

American (AMR) AF: 0.0772 AC: 3450 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4436 AN: 25888

East Asian (EAS) AF: 0.233 AC: 9199 AN: 39464

South Asian (SAS) AF: 0.158 AC: 13472 AN: 85312

European-Finnish (FIN) AF: 0.106 AC: 5632 AN: 53370

Middle Eastern (MID) AF: 0.199 AC: 1127 AN: 5666

European-Non Finnish (NFE) AF: 0.117 AC: 125173 AN: 1069510

Other (OTH) AF: 0.123 AC: 7226 AN: 58886

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

African (AFR) AF: 0.0202 AC: 840 AN: 41542

American (AMR) AF: 0.0929 AC: 1420 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 589 AN: 3470

East Asian (EAS) AF: 0.242 AC: 1249 AN: 5162

South Asian (SAS) AF: 0.164 AC: 790 AN: 4816

European-Finnish (FIN) AF: 0.0988 AC: 1044 AN: 10568

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.123 AC: 8351 AN: 67986

Other (OTH) AF: 0.106 AC: 224 AN: 2112

Alfa AF: 0.120 Hom.: 273

Bravo AF: 0.0915

Asia WGS AF: 0.160 AC: 556 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary antithrombin deficiency (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.018
DANN	Benign	0.50
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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