rs28362944

chr11-57598250-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000062.3(SERPING1):c.-21T>C variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0418 in 1,544,846 control chromosomes in the GnomAD database, including 1,559 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (93 hom., cov: 31)
  • Exomes 𝑓: 0.043 (1466 hom.)
• Consequence: SERPING1 NM_000062.3 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.0005334
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.247

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015582442).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0314 (4774/152100) while in subpopulation NFE AF= 0.0484 (3288/67970). AF 95% confidence interval is 0.047. There are 93 homozygotes in gnomad4. There are 2260 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 93 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPING1	NM_000062.3	c.-21T>C		splice_region_variant, 5_prime_UTR_variant	2/8	ENST00000278407.9
SERPING1	NM_001032295.2	c.-21T>C		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPING1	ENST00000278407.9	c.-21T>C		splice_region_variant, 5_prime_UTR_variant	2/8	1	NM_000062.3	P2

Frequencies

GnomAD3 genomes AF: 0.0314 AC: 4776 AN: 151982 Hom.: 93 Cov.: 31

Gnomad AFR AF: 0.00834

Gnomad AMI AF: 0.0771

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.000583

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0510

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0484

Gnomad OTH AF: 0.0297

GnomAD3 exomes AF: 0.0291 AC: 4285 AN: 147346 Hom.: 96 AF XY: 0.0292 AC XY: 2312 AN XY: 79186

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.0000921

Gnomad SAS exome AF: 0.00917

Gnomad FIN exome AF: 0.0498

Gnomad NFE exome AF: 0.0467

Gnomad OTH exome AF: 0.0311

GnomAD4 exome AF: 0.0429 AC: 59761 AN: 1392746 Hom.: 1466 Cov.: 31 AF XY: 0.0419 AC XY: 28767 AN XY: 686004

Gnomad4 AFR exome AF: 0.00745

Gnomad4 AMR exome AF: 0.0176

Gnomad4 ASJ exome AF: 0.0208

Gnomad4 EAS exome AF: 0.0000559

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.0537

Gnomad4 NFE exome AF: 0.0491

Gnomad4 OTH exome AF: 0.0351

GnomAD4 genome AF: 0.0314 AC: 4774 AN: 152100 Hom.: 93 Cov.: 31 AF XY: 0.0304 AC XY: 2260 AN XY: 74364

Gnomad4 AFR AF: 0.00831

Gnomad4 AMR AF: 0.0225

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.000584

Gnomad4 SAS AF: 0.00766

Gnomad4 FIN AF: 0.0510

Gnomad4 NFE AF: 0.0484

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.0436 Hom.: 192

Bravo AF: 0.0292

ESP6500AA AF: 0.00671 AC: 27

ESP6500EA AF: 0.0329 AC: 264

ExAC AF: 0.0159 AC: 1662

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2019	This variant is associated with the following publications: (PMID: 16470590, 27884173, 29676077, 27116602, 23437219, 18586324, 20804470, 8755917) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

-

- -

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
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	14
Dann	Benign	0.96
DEOGEN2	Benign	0.0065	T;T
Eigen	Benign	0.17
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.27	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	D;D;D;D;N
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.032
ClinPred		0.012	T
GERP RS		-0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00053
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28362944; hg19: chr11-57365723; COSMIC: COSV53542368; COSMIC: COSV53542368;