Genetic Variant NM_000062.3:c.1396C>A (chr11-57614474-C-A) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 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 Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SERPING1
NM_000062.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 3.23

Publications

28 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: Labcorp Genetics (formerly Invitae), ClinGen
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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

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, 0.923

PP5

Variant 11-57614474-C-A is Pathogenic according to our data. Variant chr11-57614474-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3948.Status of the report is no_assertion_criteria_provided, 0 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.1396C>A	p.Arg466Ser	missense	Exon 8 of 8	NP_000053.2	P05155-1
	SERPING1	NM_001032295.2		c.1396C>A	p.Arg466Ser	missense	Exon 7 of 7	NP_001027466.1	P05155-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPING1	ENST00000278407.9	TSL:1 MANE Select	c.1396C>A	p.Arg466Ser	missense	Exon 8 of 8	ENSP00000278407.4	P05155-1
SERPING1	ENST00000619430.2	TSL:1	c.1192C>A	p.Arg398Ser	missense	Exon 7 of 7	ENSP00000478572.2	A0A087WUD9
SERPING1	ENST00000531133.5	TSL:1	n.*765C>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000435431.1	E9PK97

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000871

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary C1 esterase inhibitor deficiency - dysfunctional factor (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

Eigen

Benign

0.018

Eigen_PC

Benign

0.072

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.20

MutationAssessor

Uncertain

2.9

PhyloP100

3.2

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.012

Polyphen

0.26

Vest4

0.75

MutPred

0.68

Gain of catalytic residue at S468 (P = 0.0876)

MVP

0.95

MPC

1.1

ClinPred

1.0

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over