Variant chr11-57614463-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 6P and 6B. PM1PM2PM5BP4_ModerateBS1

The ENST00000278407.9(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. 13/21 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
ENST00000278407.9 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.51

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000278407.9

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 id is 487524.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.1569927).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000342 (5/1461814) while in subpopulation AMR AF= 0.000112 (5/44724). AF 95% confidence interval is 0.0000436. There are 0 homozygotes in gnomad4_exome. There are 1 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPING1	NM_000062.3 linkuse as main transcript	c.1385T>C	p.Ile462Thr	missense_variant	8/8	ENST00000278407.9	NP_000053.2
SERPING1	NM_001032295.2 linkuse as main transcript	c.1385T>C	p.Ile462Thr	missense_variant	7/7		NP_001027466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPING1	ENST00000278407.9 linkuse as main transcript	c.1385T>C	p.Ile462Thr	missense_variant	8/8	1	NM_000062.3	ENSP00000278407	P2	P05155-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251312

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135854

show subpopulations

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 SAS 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:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Uncertain

0.47

T;.;.;.;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.64

T;T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.16

T;T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.4

L;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.3

N;D;N;N;N

REVEL

Benign

0.21

Sift

Benign

0.13

T;T;T;T;T

Sift4G

Uncertain

0.052

T;T;T;D;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

GERP RS

3.7

Varity_R

0.33

gMVP

0.94

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over