rs11546660

chr11-57599994-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000062.3(SERPING1):c.167T>C(p.Val56Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,614,190 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V56I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (53 hom.)
• Consequence: SERPING1 NM_000062.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.30

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041720867).
• BP6: Variant 11-57599994-T-C is Benign according to our data. Variant chr11-57599994-T-C is described in ClinVar as [Benign]. Clinvar id is 305020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-57599994-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00191 (291/152296) while in subpopulation EAS AF= 0.0484 (251/5184). AF 95% confidence interval is 0.0435. There are 5 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPING1	NM_000062.3	c.167T>C	p.Val56Ala	missense_variant	3/8	ENST00000278407.9
SERPING1	NM_001032295.2	c.167T>C	p.Val56Ala	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPING1	ENST00000278407.9	c.167T>C	p.Val56Ala	missense_variant	3/8	1	NM_000062.3	P2

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 290 AN: 152178 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0481

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00388 AC: 977 AN: 251488 Hom.: 19 AF XY: 0.00369 AC XY: 501 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0481

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00166 AC: 2422 AN: 1461894 Hom.: 53 Cov.: 33 AF XY: 0.00172 AC XY: 1253 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0510

Gnomad4 SAS exome AF: 0.00196

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152296 Hom.: 5 Cov.: 32 AF XY: 0.00219 AC XY: 163 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0484

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00237 Hom.: 20

Bravo AF: 0.00247

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00409 AC: 496

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SERPING1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Hereditary angioedema type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	0.0020
Dann	Benign	0.37
DEOGEN2	Benign	0.013	T;T;T;.;.;.;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0055	N
LIST_S2	Benign	0.40	T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0042	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.030	N;N;D;N;N;N;N;.
REVEL	Uncertain	0.35
Sift	Benign	0.25	T;T;D;T;T;D;T;.
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0030	.;B;.;.;.;.;B;.
Vest4		0.090, 0.14, 0.11, 0.13, 0.053
MVP		0.91
MPC		0.35
ClinPred		0.018	T
GERP RS		-9.5
Varity_R		0.016
gMVP		0.18

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: rs11546660; hg19: chr11-57367467; COSMIC: COSV53542711; COSMIC: COSV53542711;