chr11-57614516-G-A

Variant names:

• chr11-57614516-G-A
• rs4926
• NM_000062.3:c.1438G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BA1

The NM_000062.3(SERPING1):​c.1438G>A​(p.Val480Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,613,640 control chromosomes in the GnomAD database, including 52,717 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. V480E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.21 (3932 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48785 hom.)
• Consequence: SERPING1 NM_000062.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.19
• Publications: 66 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: Benign. The variant received -16 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000062.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-57614517-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3256140.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0052272975).
• BP6: Variant 11-57614516-G-A is Benign according to our data. Variant chr11-57614516-G-A is described in ClinVar as Benign. ClinVar VariationId is 254786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

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.1438G>A	p.Val480Met	missense	Exon 8 of 8	NP_000053.2	P05155-1
	SERPING1	NM_001032295.2		c.1438G>A	p.Val480Met	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.1438G>A	p.Val480Met	missense	Exon 8 of 8	ENSP00000278407.4	P05155-1
	SERPING1	ENST00000619430.2	TSL:1	c.1234G>A	p.Val412Met	missense	Exon 7 of 7	ENSP00000478572.2	A0A087WUD9
	SERPING1	ENST00000531133.5	TSL:1	n.*807G>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000435431.1	E9PK97

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32237 AN: 151900 Hom.: 3932 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.289

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.222 AC: 55703 AN: 250966 AF XY: 0.228

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.289

Gnomad EAS exome AF: 0.107

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.272

Gnomad OTH exome AF: 0.240

GnomAD4 exome AF: 0.253 AC: 370160 AN: 1461622 Hom.: 48785 Cov.: 34 AF XY: 0.253 AC XY: 184011 AN XY: 727102

African (AFR) AF: 0.0938 AC: 3141 AN: 33480

American (AMR) AF: 0.134 AC: 6007 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7397 AN: 26130

East Asian (EAS) AF: 0.0988 AC: 3921 AN: 39700

South Asian (SAS) AF: 0.187 AC: 16090 AN: 86256

European-Finnish (FIN) AF: 0.312 AC: 16635 AN: 53318

Middle Eastern (MID) AF: 0.264 AC: 1522 AN: 5768

European-Non Finnish (NFE) AF: 0.270 AC: 300340 AN: 1111868

Other (OTH) AF: 0.250 AC: 15107 AN: 60386

GnomAD4 genome AF: 0.212 AC: 32237 AN: 152018 Hom.: 3932 Cov.: 32 AF XY: 0.213 AC XY: 15806 AN XY: 74278

African (AFR) AF: 0.104 AC: 4317 AN: 41518

American (AMR) AF: 0.181 AC: 2764 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1002 AN: 3468

East Asian (EAS) AF: 0.112 AC: 579 AN: 5176

South Asian (SAS) AF: 0.185 AC: 890 AN: 4806

European-Finnish (FIN) AF: 0.311 AC: 3275 AN: 10514

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.274 AC: 18623 AN: 67950

Other (OTH) AF: 0.234 AC: 493 AN: 2106

Alfa AF: 0.256 Hom.: 15862

Bravo AF: 0.196

TwinsUK AF: 0.271 AC: 1005

ALSPAC AF: 0.271 AC: 1045

ESP6500AA AF: 0.106 AC: 468

ESP6500EA AF: 0.281 AC: 2413

ExAC AF: 0.222 AC: 26998

Asia WGS AF: 0.155 AC: 537 AN: 3478

EpiCase AF: 0.260

EpiControl AF: 0.259

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary angioedema type 1 (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.9
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L
PhyloP100		-1.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.20
Sift	Uncertain	0.020	D
Sift4G	Benign	0.10	T
Polyphen		0.014	B
Vest4		0.18
MPC		0.66
ClinPred		0.037	T
GERP RS		-0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.93
Mutation Taster		=97/3	polymorphism (auto)

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: rs4926; hg19: chr11-57381989; COSMIC: COSV53542407;