rs200534715

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_000062.3(SERPING1):c.352A>G(p.Thr118Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000981 in 1,498,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.000037 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

SERPING1
NM_000062.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.113

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.026393026).

BP6

Variant 11-57600179-A-G is Benign according to our data. Variant chr11-57600179-A-G is described in ClinVar as [Benign]. Clinvar id is 68250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-57600179-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000371 (5/134674) while in subpopulation EAS AF= 0.00121 (5/4132). AF 95% confidence interval is 0.000476. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPING1	NM_000062.3 linkuse as main transcript	c.352A>G	p.Thr118Ala	missense_variant	3/8	ENST00000278407.9
SERPING1	NM_001032295.2 linkuse as main transcript	c.352A>G	p.Thr118Ala	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPING1	ENST00000278407.9 linkuse as main transcript	c.352A>G	p.Thr118Ala	missense_variant	3/8	1	NM_000062.3	P2	P05155-1

Frequencies

GnomAD3 genomes

AF:

0.0000372

AC:

AN:

134576

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00121

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000227

AC:

AN:

251392

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00310

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000104

AC:

142

AN:

1364012

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

678340

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000240

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00441

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000746

GnomAD4 genome

AF:

0.0000371

AC:

AN:

134674

Hom.:

Cov.:

AF XY:

0.0000309

AC XY:

AN XY:

64678

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00121

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000113

ExAC

AF:

0.000198

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Apr 16, 2021	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Hereditary angioedema type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

Cadd

Benign

5.7

Dann

Benign

0.83

DEOGEN2

Benign

0.030

T;T;.;.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.46

T;T;T;T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.026

T;T;T;T;T;T

MetaSVM

Benign

-0.51

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.5

N;N;N;N;N;N

REVEL

Uncertain

0.57

Sift

Benign

0.041

D;T;T;T;T;T

Sift4G

Uncertain

0.055

T;T;T;T;T;T

Polyphen

0.010

.;B;.;.;.;B

Vest4

0.066, 0.079, 0.082, 0.050

MVP

1.0

MPC

0.40

ClinPred

0.011

GERP RS

-5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.044

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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