chr1-173907528-C-T

Variant names:

• chr1-173907528-C-T
• rs542881762
• NM_000488.4:c.1154-14G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PP3 PP4 PS4 PP1_Moderate PM4

This summary comes from the ClinGen Evidence Repository: The NM_000488.3(SERPINC1):c.1154-14G>A variant is completely absent from gnomAD v2.1.1 and v3.1, meeting criteria for PM2_supporting. More than 20 probands across publications and internal laboratory data meet AT deficiency phenotype criteria and therefore, PS4_Very Strong is applied. 6 segregations across 4 families are counted in the literature (PMIDs: 7981186, 15164384, 7949130, 32686144), so PP1_Moderate is applied. SpliceAI predicts a cryptic acceptor splice site at -2bp with a score of 0.5. At least 2 publications (PMID:7949130, PMID:30046692) show experimental evidence of alternative splicing in patients due to the variant and therefore, PP3 is applied. The splicing aberration results in addition of 12bp of intron 4 into exon 5 of SERPINC1, increasing the protein length by 4 amino acids. This region is noted to be important for the folding and polymerization of the protein. Therefore, PM4 is applied. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Thrombosis Variant Curation Expert Panel for SERPINC1: PS4_Very Strong, PM4, PP1_Moderate, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16609956/MONDO:0013144/084

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SERPINC1 NM_000488.4 intron
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 0.221
• Publications: 7 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: Pathogenic. The variant received 11 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: 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.1154-14G>A		intron	N/A	NP_000479.1	P01008
	SERPINC1	NM_001386302.1		c.1277-14G>A		intron	N/A	NP_001373231.1
	SERPINC1	NM_001386303.1		c.1235-14G>A		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.1154-14G>A		intron	N/A	ENSP00000356671.3	P01008
	SERPINC1	ENST00000874328.1		c.1283-14G>A		intron	N/A	ENSP00000544387.1
	SERPINC1	ENST00000874324.1		c.1277-14G>A		intron	N/A	ENSP00000544383.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458860 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726020

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109276

Other (OTH) AF: 0.00 AC: 0 AN: 60272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Hereditary antithrombin deficiency (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	22
DANN	Benign	0.50
PhyloP100		0.22
Mutation Taster		=34/66	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.50		Position offset: -2
DS_AL_spliceai		0.29		Position offset: -14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs542881762; hg19: chr1-173876666;