11-57597584-A-G

Position:

• chr11-57597584-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The ENST00000619430.2(SERPING1):​c.-161A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
• Consequence: SERPING1 ENST00000619430.2 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.18

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-57597584-A-G is Pathogenic according to our data. Variant chr11-57597584-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 3242430.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-57597584-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000619430.2	c.-161A>G		5_prime_UTR_variant	1/7	1		ENSP00000478572
SERPING1	ENST00000405496.5	c.-23+53A>G		intron_variant		4		ENSP00000384561

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152014 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152014 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74248

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

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

Jun 15, 2024

The c.-161A>G variant in SERPING1 was observed in Azerbaijanian autosomal recessive HAE family with 2 homozygous siblings. The same variant has previously been reported in Turkish autosomal recessive HAE family with 3 homozygous siblings (Büyüköztürk et all, 2009). The c.-161A>G variant was absent in 136 ethnically matched control chromosomes analyzed and was present at extremely low frequency in gnomAD v4.1.0 database (0.0002 in South Asian only). Affected members displayed a concordant complement profile with HAE-I, whereas heterozygous individuals had mild decrease of C1Inh activities within normal range. Additionally, in vitro functional studies indicate that C1INH mRNA levels in homozygous and heterozygous carriers are reduced (Büyüköztürk et all, 2009). According to our observation and the published information of Büyüköztürk et all, 2009, the c.-161A>G variant meets ACMG /ClinGen SVI guidance criteria to be classified as pathogenic: PS3, PP1_Str, PS4_Mod, PM2_Sup -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.94

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: rs1291031675; hg19: chr11-57365057;