rs4926

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBA1

The NM_000062.3(SERPING1):c.1438G>A(p.Val480Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,613,640 control chromosomes in the GnomAD database, including 52,717 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V480G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.21 ( 3932 hom., cov: 32)

Exomes 𝑓: 0.25 ( 48785 hom. )

Consequence

SERPING1
NM_000062.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.19

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 -16 ACMG points.

PM1

In a strand (size 6) in uniprot entity IC1_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000062.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-57614517-T-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0052272975).

BP6

Variant 11-57614516-G-A is Benign according to our data. Variant chr11-57614516-G-A is described in ClinVar as [Benign]. Clinvar id is 254786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-57614516-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPING1	NM_000062.3 linkuse as main transcript	c.1438G>A	p.Val480Met	missense_variant	8/8	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2 linkuse as main transcript	c.1438G>A	p.Val480Met	missense_variant	7/7		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9 linkuse as main transcript	c.1438G>A	p.Val480Met	missense_variant	8/8	1	NM_000062.3	ENSP00000278407	P2	P05155-1

Frequencies

GnomAD3 genomes

AF:

0.212

AC:

32237

AN:

151900

Hom.:

3932

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.248

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.289

Gnomad EAS

AF:

0.112

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.311

Gnomad MID

AF:

0.226

Gnomad NFE

AF:

0.274

Gnomad OTH

AF:

0.234

GnomAD3 exomes

AF:

0.222

AC:

55703

AN:

250966

Hom.:

6953

AF XY:

0.228

AC XY:

30961

AN XY:

135648

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.126

Gnomad ASJ exome

AF:

0.289

Gnomad EAS exome

AF:

0.107

Gnomad SAS exome

AF:

0.185

Gnomad FIN exome

AF:

0.318

Gnomad NFE exome

AF:

0.272

Gnomad OTH exome

AF:

0.240

GnomAD4 exome

AF:

0.253

AC:

370160

AN:

1461622

Hom.:

48785

Cov.:

AF XY:

0.253

AC XY:

184011

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.0938

Gnomad4 AMR exome

AF:

0.134

Gnomad4 ASJ exome

AF:

0.283

Gnomad4 EAS exome

AF:

0.0988

Gnomad4 SAS exome

AF:

0.187

Gnomad4 FIN exome

AF:

0.312

Gnomad4 NFE exome

AF:

0.270

Gnomad4 OTH exome

AF:

0.250

GnomAD4 genome

AF:

0.212

AC:

32237

AN:

152018

Hom.:

3932

Cov.:

AF XY:

0.213

AC XY:

15806

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.104

Gnomad4 AMR

AF:

0.181

Gnomad4 ASJ

AF:

0.289

Gnomad4 EAS

AF:

0.112

Gnomad4 SAS

AF:

0.185

Gnomad4 FIN

AF:

0.311

Gnomad4 NFE

AF:

0.274

Gnomad4 OTH

AF:

0.234

Alfa

AF:

0.261

Hom.:

6904

Bravo

AF:

0.196

TwinsUK

AF:

0.271

AC:

1005

ALSPAC

AF:

0.271

AC:

1045

ESP6500AA

AF:

0.106

AC:

468

ESP6500EA

AF:

0.281

AC:

2413

ExAC

AF:

0.222

AC:

26998

Asia WGS

AF:

0.155

AC:

537

AN:

3478

EpiCase

AF:

0.260

EpiControl

AF:

0.259

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary angioedema type 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

5.9

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;.;.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.51

T;T;T;T;T

MetaRNN

Benign

0.0052

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

L;.;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.54

N;N;N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.020

D;D;T;D;T

Sift4G

Benign

0.10

T;T;T;T;T

Polyphen

0.014

B;.;.;.;.

Vest4

0.18

MPC

0.66

ClinPred

0.037

GERP RS

-0.87

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.93

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