rs28940870

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_000062.3(SERPING1):​c.1396C>A​(p.Arg466Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R466H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SERPING1
NM_000062.3 missense

Scores

6
8
5

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 3.23
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000062.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-57614474-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.923
PP5
Variant 11-57614474-C-A is Pathogenic according to our data. Variant chr11-57614474-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 3948.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-57614474-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SERPING1NM_000062.3 linkuse as main transcriptc.1396C>A p.Arg466Ser missense_variant 8/8 ENST00000278407.9
SERPING1NM_001032295.2 linkuse as main transcriptc.1396C>A p.Arg466Ser missense_variant 7/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SERPING1ENST00000278407.9 linkuse as main transcriptc.1396C>A p.Arg466Ser missense_variant 8/81 NM_000062.3 P2P05155-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Hereditary C1 esterase inhibitor deficiency - dysfunctional factor Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 18, 1990- -
not provided Other:1
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.75
D;.;.;.;T
Eigen
Benign
0.018
Eigen_PC
Benign
0.072
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.81
T;T;T;T;T
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D
MetaSVM
Uncertain
0.20
D
MutationAssessor
Uncertain
2.9
M;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Benign
0.41
T
PROVEAN
Pathogenic
-5.3
D;D;D;D;D
REVEL
Uncertain
0.62
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Uncertain
0.012
D;D;D;D;D
Polyphen
0.26
B;.;.;.;.
Vest4
0.75
MutPred
0.68
.;.;Gain of catalytic residue at S468 (P = 0.0876);.;.;
MVP
0.95
MPC
1.1
ClinPred
1.0
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
0.96

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.

Other links and lift over

dbSNP: rs28940870; hg19: chr11-57381947; API