chr11-57598248-G-A

Variant names:

• chr11-57598248-G-A
• NM_000062.3:c.-22-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000062.3(SERPING1):​c.-22-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SERPING1 NM_000062.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.32
• Publications: 1 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: Labcorp Genetics (formerly Invitae), ClinGen
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.5, offset of 22, new splice context is: ccgctgacgtcgccgcccAGatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-57598248-G-A is Pathogenic according to our data. Variant chr11-57598248-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3253588.Status of the report is criteria_provided_single_submitter, 1 stars.

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.-22-1G>A		splice_acceptor intron	N/A	NP_000053.2	P05155-1
	SERPING1	NM_001032295.2		c.-23G>A		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.-22-1G>A		splice_acceptor intron	N/A	ENSP00000278407.4	P05155-1
	SERPING1	ENST00000619430.2	TSL:1	c.-22-1G>A		splice_acceptor intron	N/A	ENSP00000478572.2	A0A087WUD9
	SERPING1	ENST00000531797.5	TSL:1	n.-23G>A		non_coding_transcript_exon	Exon 1 of 4	ENSP00000432554.1	E9PK97

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1393350 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 686316

African (AFR) AF: 0.00 AC: 0 AN: 31536

American (AMR) AF: 0.00 AC: 0 AN: 35648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25058

East Asian (EAS) AF: 0.00 AC: 0 AN: 35760

South Asian (SAS) AF: 0.00 AC: 0 AN: 79032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4656

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075292

Other (OTH) AF: 0.00 AC: 0 AN: 57552

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary angioedema type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0080	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.28	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	-0.061	T
PhyloP100		4.3
PROVEAN	Benign	-0.090	N
REVEL	Uncertain	0.35
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Vest4		0.19
MutPred		0.24		Gain of ubiquitination at R27 (P = 0.0131)
MVP		0.91
ClinPred		0.57	D
GERP RS		5.0
PromoterAI		0.11	Neutral
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.83		Position offset: 1

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

Other links and lift over

hg19: chr11-57365721;