chr11-57598271-A-C

Variant names:

• chr11-57598271-A-C
• rs1565168898
• NM_000062.3:c.1A>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000062.3(SERPING1):​c.1A>C​(p.Met1?) variant causes a initiator codon 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 (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SERPING1 NM_000062.3 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.44

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 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 21 pathogenic variants. Next in-frame start position is after 53 codons. Genomic position: 57599984. Lost 0.104 part of the original CDS.
• PS1: Another start lost variant in NM_000062.3 (SERPING1) was described as [Pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-57598271-A-C is Pathogenic according to our data. Variant chr11-57598271-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 626353.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-57598271-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPING1	NM_000062.3	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 8	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 7		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 8	1	NM_000062.3	ENSP00000278407.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary angioedema type 1 Pathogenic:1

-

Department of Immunology and Histocompatibility, University of Thessaly

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1A>C (p.Met1Leu) variant has been previously reported in association with hereditary angioedema in the literature (Speletas et al., 2015; Loules et al., 2018). It is a regulatory mutation that alters the initiation codon of the transcript 001 of SERPING1 gene. It was detected by our laboratory in 1 male patient with C1-INH-HAE Type I and positive family history for the disease. It was not detected in a healthy family member that was also tested (patient's son). The variant has never been detected in approximately 120000 individuals of the Exome Aggregation Consortium (ExAC), indicating that it is not a common variant. There are three more mutations which change the initiation codon of the transcript and they have been previously reported in association with C1-INH HAE type I: c.1A>G (p.Met1Val), c.2T>G (p.Met1Arg) [Speletas et al. 2015] and c.2T>G (p.Met1Thr) [Bafunno V et al., 2014]. Taking all the above into account and according to ACMG Guidelines (Criteria: PVS1, PS1, PS4, PM2, PP1-S, PP4) the variant is considered pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.061	T;T;T;.;.;T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;T;D;D;T;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.050	D
PROVEAN	Benign	-1.1	N;N;N;N;N;N;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D;D;D;T;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.77, 0.87	.;P;.;.;.;P;.
Vest4		0.77, 0.81, 0.80, 0.44, 0.43
MutPred		0.38		.;.;Loss of catalytic residue at M35 (P = 0.0016);.;.;Loss of catalytic residue at M35 (P = 0.0016);.;
MVP		0.97
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.86
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1565168898; hg19: chr11-57365744;