NM_000062.3:c.1030-1222A>G

Variant names:

• chr11-57610495-A-G
• rs3824988
• NM_000062.3:c.1030-1222A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000062.3(SERPING1):​c.1030-1222A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,194 control chromosomes in the GnomAD database, including 3,917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.21 (3917 hom., cov: 32)
• Consequence: SERPING1 NM_000062.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.44
• Publications: 17 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 11-57610495-A-G is Benign according to our data. Variant chr11-57610495-A-G is described in ClinVar as Benign. ClinVar VariationId is 983232.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPING1	NM_000062.3	MANE Select	c.1030-1222A>G		intron	N/A	NP_000053.2
	SERPING1	NM_001032295.2		c.1030-1222A>G		intron	N/A	NP_001027466.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPING1	ENST00000278407.9	TSL:1 MANE Select	c.1030-1222A>G		intron	N/A	ENSP00000278407.4
	SERPING1	ENST00000619430.2	TSL:1	c.826-1222A>G		intron	N/A	ENSP00000478572.2
	SERPING1	ENST00000531133.5	TSL:1	n.*399-1222A>G		intron	N/A	ENSP00000435431.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32236 AN: 152076 Hom.: 3917 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: 0.184

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.231

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.212 AC: 32234 AN: 152194 Hom.: 3917 Cov.: 32 AF XY: 0.213 AC XY: 15821 AN XY: 74418

African (AFR) AF: 0.104 AC: 4305 AN: 41536

American (AMR) AF: 0.181 AC: 2765 AN: 15288

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

East Asian (EAS) AF: 0.113 AC: 584 AN: 5184

South Asian (SAS) AF: 0.183 AC: 884 AN: 4818

European-Finnish (FIN) AF: 0.311 AC: 3294 AN: 10598

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

European-Non Finnish (NFE) AF: 0.274 AC: 18614 AN: 67980

Other (OTH) AF: 0.232 AC: 489 AN: 2112

Alfa AF: 0.235 Hom.: 2562

Bravo AF: 0.196

Asia WGS AF: 0.155 AC: 536 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary angioedema type 1 Benign:1

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.15
DANN	Benign	0.38
PhyloP100		-1.4
Mutation Taster		=100/0	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: rs3824988; hg19: chr11-57377968;