11-57598272-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000062.3(SERPING1):c.2T>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)
• Consequence: SERPING1 NM_000062.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.566

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 14 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 626352
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-57598272-T-G is Pathogenic according to our data. Variant chr11-57598272-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 2910260.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-57598272-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 05, 2023

For these reasons, this variant has been classified as Pathogenic. Disruption of the initiator codon has been observed in individuals with hereditary angioedema (PMID: 18535392, 21832835, 24456027; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SERPING1 mRNA. The next in-frame methionine is located at codon 53. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.043	T;T;T;.;.;T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;T;D;D;T;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-1.6	N;N;D;N;N;N;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.98, 0.99	.;D;.;.;.;D;.
Vest4		0.82, 0.76, 0.80, 0.68, 0.60
MutPred		0.47		.;.;Loss of catalytic residue at M35 (P = 0.0189);.;.;Loss of catalytic residue at M35 (P = 0.0189);.;
MVP		0.90
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.96
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-57365745;