rs281875178

Positions:

• chr11-57614568-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1_Moderate PM2 PP5_Moderate

The NM_000062.3(SERPING1):​c.1490A>G​(p.Asp497Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPING1 NM_000062.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 5.79

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript NM_000062.3 (SERPING1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-57614568-A-G is Pathogenic according to our data. Variant chr11-57614568-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68249.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPING1	NM_000062.3	c.1490A>G	p.Asp497Gly	missense_variant	8/8	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2	c.1490A>G	p.Asp497Gly	missense_variant	7/7		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9	c.1490A>G	p.Asp497Gly	missense_variant	8/8	1	NM_000062.3	ENSP00000278407.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary angioedema type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

DNA-diagnostics Laboratory, Research Centre For Medical Genetics

Jun 01, 2024

According to our observation and the published information of Xu et all, 2012, the c.1490A>G variant in SERPING1 meets ACMG/ClinGen SVI guidance criteria to be classified as likely pathogenic: PP4_Str, PS4_Mod, PM2_Sup, PP2, PP3 -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.;.;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.011	D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		0.82	P;.;.;.;.
Vest4		0.56
MutPred		0.61		.;.;Gain of catalytic residue at D502 (P = 0.0296);.;.;
MVP		0.97
MPC		1.1
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.99

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: rs281875178; hg19: chr11-57382041;