rs114788552

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001080451.2(SERPINA11):​c.667C>T​(p.Arg223Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R223G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

SERPINA11
NM_001080451.2 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.424
Variant links:
Genes affected
SERPINA11 (HGNC:19193): (serpin family A member 11) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06122452).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SERPINA11NM_001080451.2 linkc.667C>T p.Arg223Cys missense_variant Exon 3 of 5 ENST00000334708.4 NP_001073920.1
SERPINA11NM_001429948.1 linkc.55C>T p.Arg19Cys missense_variant Exon 3 of 5 NP_001416877.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SERPINA11ENST00000334708.4 linkc.667C>T p.Arg223Cys missense_variant Exon 3 of 5 1 NM_001080451.2 ENSP00000335024.3 Q86U17
ENSG00000256357ENST00000536735.1 linkn.171+14840G>A intron_variant Intron 2 of 2 4

Frequencies

GnomAD3 genomes
AF:
0.000283
AC:
43
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000989
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000558
AC:
14
AN:
250854
Hom.:
0
AF XY:
0.0000590
AC XY:
8
AN XY:
135556
show subpopulations
Gnomad AFR exome
AF:
0.000492
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000417
AC:
61
AN:
1461650
Hom.:
0
Cov.:
33
AF XY:
0.0000330
AC XY:
24
AN XY:
727120
show subpopulations
Gnomad4 AFR exome
AF:
0.000867
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.000215
GnomAD4 genome
AF:
0.000302
AC:
46
AN:
152320
Hom.:
0
Cov.:
32
AF XY:
0.000362
AC XY:
27
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.00103
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000611
Hom.:
0
Bravo
AF:
0.000363
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000741
AC:
9
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 03, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.667C>T (p.R223C) alteration is located in exon 3 (coding exon 2) of the SERPINA11 gene. This alteration results from a C to T substitution at nucleotide position 667, causing the arginine (R) at amino acid position 223 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.094
T
Eigen
Benign
-0.011
Eigen_PC
Benign
-0.099
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.69
T
M_CAP
Uncertain
0.098
D
MetaRNN
Benign
0.061
T
MetaSVM
Uncertain
-0.23
T
MutationAssessor
Uncertain
2.1
M
PrimateAI
Benign
0.22
T
PROVEAN
Benign
-1.8
N
REVEL
Uncertain
0.43
Sift
Benign
0.10
T
Sift4G
Uncertain
0.035
D
Polyphen
0.84
P
Vest4
0.18
MVP
0.74
MPC
0.073
ClinPred
0.069
T
GERP RS
4.5
Varity_R
0.20
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.15
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.

Other links and lift over

dbSNP: rs114788552; hg19: chr14-94912918; COSMIC: COSV100593897; API