dbSNP rs121907950: SERPING1:p.Ala465Gly (chr11-57614472-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000062.3(SERPING1):c.1394C>G(p.Ala465Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A465V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SERPING1
NM_000062.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.36

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hereditary angioedema with C1Inh deficiency
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
C1 inhibitor deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary angioedema type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary angioedema type 2
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SERPING1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000062.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3567149).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPING1	NM_000062.3 link	c.1394C>G	p.Ala465Gly	missense_variant	Exon 8 of 8	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2 link	c.1394C>G	p.Ala465Gly	missense_variant	Exon 7 of 7		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9 link	c.1394C>G	p.Ala465Gly	missense_variant	Exon 8 of 8	1	NM_000062.3	ENSP00000278407.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

T;.;.;.;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.67

T;T;T;T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.36

T;T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.8

L;.;.;.;.

PhyloP100

3.4

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.4

N;N;N;N;D

REVEL

Uncertain

0.30

Sift

Benign

0.10

T;T;T;T;T

Sift4G

Benign

0.10

T;T;T;T;T

Polyphen

0.0020

B;.;.;.;.

Vest4

0.22

MutPred

0.47

.;.;Gain of sheet (P = 0.0827);.;.;

MVP

0.58

MPC

0.61

ClinPred

0.85

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.60

gMVP

0.92

Mutation Taster

=34/66

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over