11-57598272-TGGCCTCCA-T

Position:

• chr11-57598272-TGGCCTCCA-T

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.6_13del​(p.Ser3_?5) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SERPING1 NM_000062.3 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.49

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: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 413 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_000062.3 (SERPING1) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-57598272-TGGCCTCCA-T is Pathogenic according to our data. Variant chr11-57598272-TGGCCTCCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 3336827.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-57598272-TGGCCTCCA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPING1	NM_000062.3	c.6_13del	p.Ser3_?5	frameshift_variant, start_lost	2/8	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2	c.6_13del	p.Ser3_?5	frameshift_variant, start_lost	1/7		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9	c.6_13del	p.Ser3_?5	frameshift_variant, start_lost	2/8	1	NM_000062.3	ENSP00000278407	P2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary angioedema type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

DNA-diagnostics Laboratory, Research Centre For Medical Genetics

Aug 10, 2024

The pathogenic or likely pathogenic SERPING1 gene variants are detected in >90% of the HAE1/2 families and in >80% of the total HAE families (e.g., DOI: 10.1016/j.molimm.2008.05.007, 10.1159/2F000138883, 10.1016/j.molimm.2011.07.010). Across all SERPING1 gene exons, about 50% of the pathogenic or likely pathogenic variants associated with HAE are LoF (173/297 in ClinVar or 292/596 in HGMD 2022.1). In our study, the heterozygous c.6_13del (p.Ser3Aspfs*14) variant in SERPING1 was observed in 1 HAE1 patient with an unknown family HAE history. According to our observation the c.6_13del variant in SERPING1 meets ACMG/ClinGen SVI guidance criteria to be classified as pathogenic: PVS1, PP4_Mod, PM2_Sup -

Computational scores

Source: dbNSFP v4.3

Splicing

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;