rs1554995255

Positions:

• chr11-57602071-T-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 (★). Synonymous variant affecting the same amino acid position (i.e. I196I) has been classified as Likely benign.

• 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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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/exons	MANE	UniProt
SERPING1	NM_000062.3	c.587T>A	p.Ile196Asn	missense_variant	4/8	ENST00000278407.9
SERPING1	NM_001032295.2	c.587T>A	p.Ile196Asn	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPING1	ENST00000278407.9	c.587T>A	p.Ile196Asn	missense_variant	4/8	1	NM_000062.3	P2

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

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 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

Uncertain significance, no assertion criteria provided

research

Central Haematology Laboratory, Luzerner Kantonsspital

Oct 07, 2013

- -

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;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
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;