11-57614475-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV000576548: 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).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R466H) has been classified as 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
• 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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000576548: 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).
• PM1: In a hotspot region, there are 11 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-57614475-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3946.
• 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 VariationId is 426171.Status of the report is criteria_provided_single_submitter, 1 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.1397G>C	p.Arg466Pro	missense	Exon 8 of 8	NP_000053.2	P05155-1
	SERPING1	NM_001032295.2		c.1397G>C	p.Arg466Pro	missense	Exon 7 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.1397G>C	p.Arg466Pro	missense	Exon 8 of 8	ENSP00000278407.4	P05155-1
	SERPING1	ENST00000619430.2	TSL:1	c.1193G>C	p.Arg398Pro	missense	Exon 7 of 7	ENSP00000478572.2	A0A087WUD9
	SERPING1	ENST00000531133.5	TSL:1	n.*766G>C		non_coding_transcript_exon	Exon 6 of 6	ENSP00000435431.1	E9PK97

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.012
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.0078	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.2
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121907948; hg19: chr11-57381948;