chr11-57602071-T-A

Variant names:

• chr11-57602071-T-A
• rs1554995255
• NM_000062.3:c.587T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_000062.3(SERPING1):​c.587T>A​(p.Ile196Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SERPING1 NM_000062.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.06

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 10) in uniprot entity IC1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000062.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-57602071-T-A is Pathogenic according to our data. Variant chr11-57602071-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 252940.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-57602071-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPING1	NM_000062.3	c.587T>A	p.Ile196Asn	missense_variant	Exon 4 of 8	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2	c.587T>A	p.Ile196Asn	missense_variant	Exon 3 of 7		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9	c.587T>A	p.Ile196Asn	missense_variant	Exon 4 of 8	1	NM_000062.3	ENSP00000278407.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Angioedema Pathogenic:1

Jun 01, 2024

DNA-diagnostics Laboratory, Research Centre For Medical Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

According to our observation and the published information of Steiner et all, 2017 and Ponard et all, 2020, the c.587T>A variant in SERPING1 meets ACMG/ClinGen SVI guidance criteria to be classified as likely pathogenic: PS4_Mod, PP1_Mod, PP4_Mod, PP2, PM2_Sup -

Hereditary angioedema type 1 Uncertain:1

Oct 07, 2013

Central Haematology Laboratory, Luzerner Kantonsspital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	0.0036	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;.;.;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T;T;T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.4	L;.;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.028	B;.;.;.;D
Vest4		0.53
MutPred		0.68		.;.;.;.;Gain of disorder (P = 0.0066);
MVP		0.84
MPC		1.3
ClinPred		0.97	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.81

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: rs1554995255; hg19: chr11-57369544;