11-57606859-T-C

Variant names:

• chr11-57606859-T-C
• rs11603020
• NM_000062.3:c.1029+312T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000062.3(SERPING1):​c.1029+312T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 599,040 control chromosomes in the GnomAD database, including 17,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3924 hom., cov: 32)
  • Exomes 𝑓: 0.24 (13649 hom.)
• Consequence: SERPING1 NM_000062.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.502
• Publications: 25 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 Classification: DEFINITIVE, STRONG Submitted by: ClinGen, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-57606859-T-C is Benign according to our data. Variant chr11-57606859-T-C is described in ClinVar as Benign. ClinVar VariationId is 983254.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPING1	NM_000062.3	c.1029+312T>C		intron_variant	Intron 6 of 7	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2	c.1029+312T>C		intron_variant	Intron 5 of 6		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9	c.1029+312T>C		intron_variant	Intron 6 of 7	1	NM_000062.3	ENSP00000278407.4

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32255 AN: 152082 Hom.: 3924 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: 0.113

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.232

GnomAD4 exome AF: 0.239 AC: 106712 AN: 446840 Hom.: 13649 AF XY: 0.239 AC XY: 58370 AN XY: 244582

African (AFR) AF: 0.0988 AC: 1348 AN: 13650

American (AMR) AF: 0.137 AC: 4316 AN: 31466

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 4872 AN: 16898

East Asian (EAS) AF: 0.0971 AC: 2156 AN: 22202

South Asian (SAS) AF: 0.190 AC: 11570 AN: 61014

European-Finnish (FIN) AF: 0.309 AC: 6815 AN: 22086

Middle Eastern (MID) AF: 0.271 AC: 965 AN: 3564

European-Non Finnish (NFE) AF: 0.273 AC: 68758 AN: 251686

Other (OTH) AF: 0.244 AC: 5912 AN: 24274

GnomAD4 genome AF: 0.212 AC: 32255 AN: 152200 Hom.: 3924 Cov.: 32 AF XY: 0.213 AC XY: 15828 AN XY: 74426

African (AFR) AF: 0.104 AC: 4318 AN: 41544

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

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 1002 AN: 3472

East Asian (EAS) AF: 0.113 AC: 584 AN: 5186

South Asian (SAS) AF: 0.184 AC: 890 AN: 4830

European-Finnish (FIN) AF: 0.311 AC: 3289 AN: 10588

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18620 AN: 67982

Other (OTH) AF: 0.232 AC: 491 AN: 2112

Alfa AF: 0.231 Hom.: 2587

Bravo AF: 0.196

Asia WGS AF: 0.154 AC: 535 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary angioedema type 1 Benign:1

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CeMIA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (BA1), allele frequency is greater than expected for disorder (BS1), it is observed in a healthy adult individual (BS2), it is predicted to be benign by multiple in silico algorithms (BP4), it is found in a case with an alternate molecular basis for the disease (BP5) and/or reputable source recently reports variant as benign (BP6). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.9
DANN	Benign	0.74
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11603020; hg19: chr11-57374332;