1-173907528-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2_Supporting PS4 PP1_Moderate PM4 PP3 PP4

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

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 Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINC1	NM_000488.4	c.1154-14G>A		intron_variant	Intron 5 of 6	ENST00000367698.4	NP_000479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINC1	ENST00000367698.4	c.1154-14G>A		intron_variant	Intron 5 of 6	1	NM_000488.4	ENSP00000356671.3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary antithrombin deficiency Pathogenic:4

Aug 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 5 of the SERPINC1 gene. It does not directly change the encoded amino acid sequence of the SERPINC1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with antithrombin III deficiency (PMID: 7949130, 7981186, 8217824, 15164384, 23358206, 29662868, 30046692). It has also been observed to segregate with disease in related individuals. This variant is also known as 9788G>A. ClinVar contains an entry for this variant (Variation ID: 410384). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 7949130, 7981186). For these reasons, this variant has been classified as Pathogenic. -

Sep 21, 2023

Clingen Thrombosis Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Apr 03, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Intron variant In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.50 (>=0.2, moderate evidence for spliceogenicity)]. The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000410384 /PMID: 7949130). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	22
DANN	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs542881762; hg19: chr1-173876666;