chr11-57598275-C-T

Position:

chr11-57598275-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000062.3(SERPING1):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,557,632 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0013 ( 5 hom. )

Consequence

SERPING1
NM_000062.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.16

Variant links:

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]

SERPING1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a signal_peptide (size 21) in uniprot entity IC1_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_000062.3

BP4

Computational evidence support a benign effect (MetaRNN=0.02144134).

BP6

Variant 11-57598275-C-T is Benign according to our data. Variant chr11-57598275-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 305016.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000992 (151/152270) while in subpopulation SAS AF= 0.00228 (11/4824). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPING1	NM_000062.3 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	2/8	ENST00000278407.9
SERPING1	NM_001032295.2 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPING1	ENST00000278407.9 linkuse as main transcript	c.5C>T	p.Ala2Val	missense_variant	2/8	1	NM_000062.3	P2	P05155-1

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

151

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00125

AC:

201

AN:

160658

Hom.:

AF XY:

0.00151

AC XY:

130

AN XY:

86220

show subpopulations

Gnomad AFR exome

AF:

0.000118

Gnomad AMR exome

AF:

0.000588

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00358

Gnomad FIN exome

AF:

0.000791

Gnomad NFE exome

AF:

0.00127

Gnomad OTH exome

AF:

0.00204

GnomAD4 exome

AF:

0.00135

AC:

1897

AN:

1405362

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

954

AN XY:

693868

show subpopulations

Gnomad4 AFR exome

AF:

0.000187

Gnomad4 AMR exome

AF:

0.000710

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00324

Gnomad4 FIN exome

AF:

0.000961

Gnomad4 NFE exome

AF:

0.00135

Gnomad4 OTH exome

AF:

0.00134

GnomAD4 genome

AF:

0.000992

AC:

151

AN:

152270

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00134

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.00111

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000235

AC:

ESP6500EA

AF:

0.00107

AC:

ExAC

AF:

0.000790

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2020	Reported in patients with angioedema in published literature; observed in the unaffected father of one patient (Gosswein et al., 2008; Rasmussen et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32896191, 31488451, 18758157) -

C1 inhibitor deficiency;C2717906:Hereditary angioedema type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

SERPING1 NM_000062.2 exon 2 p.Ala2Val (c.5C>T): This variant has been reported in the literature in 2 individuals with hereditary angioedema, segregating with disease in at least 2 affected family members (Gosswein 2008 PMID:18758157). However, this variant is present in 0.3% (84/23494) of South Asian alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs185342631). This variant is present in ClinVar (Variation ID:305016). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Hereditary angioedema type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.058

T;T;T;.;.;T;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.62

T;T;T;T;T;T;T

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.021

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.085

MutationAssessor

Uncertain

2.2

.;M;.;.;M;.;.

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.4

N;N;N;N;N;N;.

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D;D;D;D;D;.

Sift4G

Uncertain

0.044

D;D;D;D;D;D;D

Polyphen

0.99

.;D;.;.;.;D;.

Vest4

0.53, 0.52, 0.49, 0.70, 0.40

MVP

0.91

MPC

0.58

ClinPred

0.042

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.36

gMVP

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over