rs281875171

Variant names:

• chr11-57606013-T-C
• rs281875171
• NM_000062.3:c.689T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000062.3(SERPING1):​c.689T>C​(p.Leu230Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPING1 NM_000062.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 4.39
• Publications: 2 publications found

Genes affected

SERPING1 (HGNC:1228): (serpin family G member 1) This gene encodes a highly glycosylated plasma protein involved in the regulation of the complement cascade. Its encoded protein, C1 inhibitor, inhibits activated C1r and C1s of the first complement component and thus regulates complement activation. It is synthesized in the liver, and its deficiency is associated with hereditary angioneurotic oedema (HANE). Alternative splicing results in multiple transcript variants encoding the same isoform. [provided by RefSeq, May 2020]

SERPING1 Gene-Disease associations (from GenCC):

• hereditary angioedema with C1Inh deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• C1 inhibitor deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary angioedema type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary angioedema type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000062.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-57606013-T-C is Pathogenic according to our data. Variant chr11-57606013-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 68254.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPING1	NM_000062.3	c.689T>C	p.Leu230Pro	missense_variant	Exon 5 of 8	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2	c.689T>C	p.Leu230Pro	missense_variant	Exon 4 of 7		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9	c.689T>C	p.Leu230Pro	missense_variant	Exon 5 of 8	1	NM_000062.3	ENSP00000278407.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary angioedema type 1 Pathogenic:1

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DNA-diagnostics Laboratory, Research Centre For Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The pathogenic or likely pathogenic SERPING1 gene variants are detected in >90% of the HAE1/2 families and in >80% of the total HAE families (e.g., DOI: 10.1016/j.molimm.2008.05.007, 10.1159/2F000138883, 10.1016/j.molimm.2011.07.010). In our study the heterozygous c.689T>C (p.Leu230Pro) variant in SERPING1 was observed in 1 HAE1 family (in 2 siblings and their father). The same variant has previously been reported in 4 HAE1 cases (DOI: 10.1016/j.molimm.2011.07.010, 10.1111/all.13699, 10.1111/all.12024, 10.1002/humu.23917). In summary, the c.689T>C variant meets ACMG/ClinGen SVI guidance criteria to be classified as pathogenic: PP4_Str, PM6, PS4_Mod, PP3_Mod, PM2_Sup, PP1 -

not provided Other:1

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.71	T;T;T;T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.
PhyloP100		4.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.90
MutPred		0.94		.;.;.;.;Gain of disorder (P = 0.0172);
MVP		0.99
MPC		1.3
ClinPred		0.98	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.88
Mutation Taster		=1/99	disease causing

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: rs281875171; hg19: chr11-57373486;