11-57614475-G-C

Variant names:

• chr11-57614475-G-C
• rs121907948
• NM_000062.3:c.1397G>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000062.3(SERPING1):​c.1397G>C​(p.Arg466Pro) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R466L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPING1 NM_000062.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.21

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a site Reactive bond for chymotrypsin (size 1) in uniprot entity IC1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936
• PP5: Variant 11-57614475-G-C is Pathogenic according to our data. Variant chr11-57614475-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 426171.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-57614475-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPING1	NM_000062.3	c.1397G>C	p.Arg466Pro	missense_variant	Exon 8 of 8	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2	c.1397G>C	p.Arg466Pro	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	c.1397G>C	p.Arg466Pro	missense_variant	Exon 8 of 8	1	NM_000062.3	ENSP00000278407.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 28, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R466P variant has been published previously as R444P in association with hereditary angioedema type II (Blanch et al., 2002). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R466P is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. The R466 residue is the P1 reactive site residue, and variants at this position interfere with normal protein function (Skriver et al., 1989). Additionally, tn silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (R466C/S/G/H/L) and in nearby residues (A461P/V, I462S, A465V, T467P) have been reported in the Human Gene Mutation Database in association with hereditary angioedema (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;.;.;T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	-0.0078	T
MutationAssessor	Pathogenic	3.1	M;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.1	D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D
Polyphen		0.054	B;.;.;.;.
Vest4		0.76
MutPred		0.68		.;.;Gain of glycosylation at T472 (P = 0.0354);.;.;
MVP		0.96
MPC		1.2
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.99
gMVP		0.98

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

Other links and lift over

dbSNP: rs121907948; hg19: chr11-57381948;