chr11-57598250-T-C

Variant names:

• chr11-57598250-T-C
• rs28362944
• NM_000062.3:c.-21T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000062.3(SERPING1):​c.-21T>C variant causes a splice region 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
• Scores: Splicing: ADA: 0.0005334
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.247
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015582442).
• BP6: Variant 11-57598250-T-C is Benign according to our data. Variant chr11-57598250-T-C is described in ClinVar as Benign. ClinVar VariationId is 305015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4774 AD gene.

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.-21T>C		splice_region	Exon 2 of 8	NP_000053.2	P05155-1
	SERPING1	NM_000062.3	MANE Select	c.-21T>C		5_prime_UTR	Exon 2 of 8	NP_000053.2	P05155-1
	SERPING1	NM_001032295.2		c.-21T>C		5_prime_UTR	Exon 1 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.-21T>C		splice_region	Exon 2 of 8	ENSP00000278407.4	P05155-1
	SERPING1	ENST00000619430.2	TSL:1	c.-21T>C		splice_region	Exon 2 of 7	ENSP00000478572.2	A0A087WUD9
	SERPING1	ENST00000278407.9	TSL:1 MANE Select	c.-21T>C		5_prime_UTR	Exon 2 of 8	ENSP00000278407.4	P05155-1

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

GnomAD2 exomes AF: 0.0291 AC: 4285 AN: 147346 AF XY: 0.0292

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 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

African (AFR) AF: 0.00745 AC: 235 AN: 31540

American (AMR) AF: 0.0176 AC: 629 AN: 35638

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 520 AN: 25046

East Asian (EAS) AF: 0.0000559 AC: 2 AN: 35768

South Asian (SAS) AF: 0.0105 AC: 829 AN: 79036

European-Finnish (FIN) AF: 0.0537 AC: 2612 AN: 48670

Middle Eastern (MID) AF: 0.0329 AC: 152 AN: 4626

European-Non Finnish (NFE) AF: 0.0491 AC: 52764 AN: 1074900

Other (OTH) AF: 0.0351 AC: 2018 AN: 57522

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

African (AFR) AF: 0.00831 AC: 345 AN: 41500

American (AMR) AF: 0.0225 AC: 344 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.000584 AC: 3 AN: 5138

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4828

European-Finnish (FIN) AF: 0.0510 AC: 541 AN: 10598

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0484 AC: 3288 AN: 67970

Other (OTH) AF: 0.0294 AC: 62 AN: 2108

Alfa AF: 0.0412 Hom.: 248

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary angioedema type 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.0065	T
Eigen	Benign	0.17
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.60	T
PhyloP100		0.25
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.032
ClinPred		0.012	T
GERP RS		-0.41
PromoterAI		0.20	Neutral
Mutation Taster		=294/6	polymorphism (auto)

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

Other links and lift over

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