chr11-57598248-G-A

Position:

• chr11-57598248-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000062.3(SERPING1):​c.-22-1G>A variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. 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 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.32

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.5, offset of 22, new splice context is: ccgctgacgtcgccgcccAGatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-57598248-G-A is Pathogenic according to our data. Variant chr11-57598248-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3253588.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-57598248-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPING1	NM_000062.3	c.-22-1G>A		splice_acceptor_variant		ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2	c.-23G>A		5_prime_UTR_variant	1/7		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9	c.-22-1G>A		splice_acceptor_variant		1	NM_000062.3	ENSP00000278407	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1393350 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 686316

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: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

Jul 14, 2024

According to the published information of Verpy et al., 1996, Duponchel et al., 2006, Gösswein et al., 2008, Loules et al., 2018, the c.-22-1G>A variant in SERPING1 meets ACMG/ClinGen SVI guidance criteria to be classified as pathogenic: PVS1, PP4_Str, PS4_Mod, PM2_Sup -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0080	T;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.28	T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	-0.061	T
MutationTaster	Benign	1.0	D;D;D;D;N
PROVEAN	Benign	-0.090	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.11	T;T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.19
MutPred		0.24		Gain of ubiquitination at R27 (P = 0.0131);Gain of ubiquitination at R27 (P = 0.0131);
MVP		0.91
ClinPred		0.57	D
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.83		Position offset: 1

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: chr11-57365721;