11-57598271-A-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000062.3(SERPING1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. 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: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SERPING1 NM_000062.3 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.44

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000062.3 (SERPING1) was described as [Pathogenic] in ClinVar as 626353
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-57598271-A-G is Pathogenic according to our data. Variant chr11-57598271-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 626352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-57598271-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPING1	NM_000062.3	c.1A>G	p.Met1?	start_lost	2/8	ENST00000278407.9
SERPING1	NM_001032295.2	c.1A>G	p.Met1?	start_lost	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPING1	ENST00000278407.9	c.1A>G	p.Met1?	start_lost	2/8	1	NM_000062.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1401342 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 691272

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

This sequence change affects the initiator methionine of the SERPING1 mRNA. The next in-frame methionine is located at codon 53. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with hereditary angioedema (PMID: 18535392, 21832835, 24456027; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 626352). For these reasons, this variant has been classified as Pathogenic. -

Hereditary angioedema type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Immunology and Histocompatibility, University of Thessaly

-

The c.1A>G (p.Met1Val) variant has been previously reported in association with hereditary angioedema in the literature (Gosswein et al., 2008; Loules et al., 2018) and in HAE database (http://hae.enzim.hu/detail.php?id=17). It is a regulatory mutation that alters the initiation codon of the transcript 001 of SERPING1 gene. It was detected by our laboratory in 6 patients with C1-INH HAE Type I, members of a Greek family (3 male and 3 female). The mutation was not detected in three asymptomatic family members. The variant has never been detected in approximately 120000 individuals of the Exome Aggregation Consortium (ExAC), indicating that it is not a common variant. There are three more mutations which change the initiation codon of the transcript and they have been previously reported in association with C1-INH HAE Type I: c.1A>C (p.Met1Leu), c.2T>G (p.Met1Arg) [Speletas et al., 2015] and c.2T>G (p.Met1Thr) [Bafunno V et al., 2014]. Taking all the above into account and according to ACMG Guidelines (Criteria: PVS1, PS1, PS4, PM2, PP1, PP4) the variant is considered pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.056	T;T;T;.;.;T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D;D;T;D;D;T;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationTaster	Benign	1.0	D;D;D;D;N
PROVEAN	Benign	-0.94	N;N;N;N;N;N;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.89, 0.94	.;P;.;.;.;P;.
Vest4		0.64, 0.70, 0.70, 0.60, 0.36
MutPred		0.35		.;.;Loss of catalytic residue at V31 (P = 0.0239);.;.;Loss of catalytic residue at V31 (P = 0.0239);.;
MVP		0.97
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.84
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1565168898; hg19: chr11-57365744;