rs763451792

Variant names:

• chr11-57614463-T-C
• rs763451792
• NM_000062.3:c.1385T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-57614463-T-C
• chr11-57614463-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 6P and 6B. PM1 PM2 PM5 BP4_Moderate BS2

The NM_000062.3(SERPING1):​c.1385T>C​(p.Ile462Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I462S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SERPING1 NM_000062.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.51
• Publications: 3 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000062.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-57614463-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 487524.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1569927).
• BS2: High AC in GnomAdExome4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPING1	NM_000062.3	MANE Select	c.1385T>C	p.Ile462Thr	missense	Exon 8 of 8	NP_000053.2
	SERPING1	NM_001032295.2		c.1385T>C	p.Ile462Thr	missense	Exon 7 of 7	NP_001027466.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPING1	ENST00000278407.9	TSL:1 MANE Select	c.1385T>C	p.Ile462Thr	missense	Exon 8 of 8	ENSP00000278407.4
	SERPING1	ENST00000619430.2	TSL:1	c.1181T>C	p.Ile394Thr	missense	Exon 7 of 7	ENSP00000478572.2
	SERPING1	ENST00000531133.5	TSL:1	n.*754T>C		non_coding_transcript_exon	Exon 6 of 6	ENSP00000435431.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251312 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Benign	0.86
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.5
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.21
Sift	Benign	0.13	T
Sift4G	Uncertain	0.052	T
Polyphen		0.030	B
Vest4		0.040
MutPred		0.63		Gain of disorder (P = 0.0191)
MVP		0.63
MPC		0.62
ClinPred		0.14	T
GERP RS		3.7
Varity_R		0.33
gMVP		0.94
Mutation Taster		=28/72	disease causing

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: rs763451792; hg19: chr11-57381936;