rs281875170

Variant names:

• chr11-57600377-G-A
• rs281875170
• NM_000062.3:c.550G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-57600377-G-A
• chr11-57600377-G-T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000062.3(SERPING1):​c.550G>A​(p.Gly184Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 15/26 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000582966: Functional studies show that healthy controls have both the full SERPING1 protein and low levels of a protein variant missing exon 3. The presence of G184R disproportionately increases the percentage of exon 3 skipping variant while decreasing the overall amount of SERPING1 protein (de la Cruz et al., 2012)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G184W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SERPING1 NM_000062.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 5.17
• Publications: 18 publications found

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, SD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, 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

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000582966: Functional studies show that healthy controls have both the full SERPING1 protein and low levels of a protein variant missing exon 3. The presence of G184R disproportionately increases the percentage of exon 3 skipping variant while decreasing the overall amount of SERPING1 protein (de la Cruz et al., 2012).; SCV001587489: Experimental studies have shown that this missense change affects SERPING1 function (PMID: 30398465).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 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 chr11-57600377-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2137092.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-57600377-G-A is Pathogenic according to our data. Variant chr11-57600377-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000062.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPING1	NM_000062.3	MANE Select	c.550G>A	p.Gly184Arg	missense splice_region	Exon 3 of 8	NP_000053.2	P05155-1
	SERPING1	NM_001032295.2		c.550G>A	p.Gly184Arg	missense splice_region	Exon 2 of 7	NP_001027466.1	P05155-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPING1	ENST00000278407.9	TSL:1 MANE Select	c.550G>A	p.Gly184Arg	missense splice_region	Exon 3 of 8	ENSP00000278407.4	P05155-1
	SERPING1	ENST00000619430.2	TSL:1	c.550G>A	p.Gly184Arg	missense splice_region	Exon 3 of 7	ENSP00000478572.2	A0A087WUD9
	SERPING1	ENST00000531133.5	TSL:1	n.52-1658G>A		intron	N/A	ENSP00000435431.1	E9PK97

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (4)
1	-	-	Hereditary angioedema type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.97		Gain of catalytic residue at G218 (P = 0.1604)
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
Splicevardb		3.0
SpliceAI score (max)		0.53		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.53		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs281875170; hg19: chr11-57367850; COSMIC: COSV53542890; COSMIC: COSV53542890;