10-80155890-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_145868.2(ANXA11):​c.1481G>A​(p.Arg494Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ANXA11
NM_145868.2 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.73
Variant links:
Genes affected
ANXA11 (HGNC:535): (annexin A11) This gene encodes a member of the annexin family, a group of calcium-dependent phospholipid-binding proteins. Annexins have unique N-terminal domains and conserved C-terminal domains, which contain calcium-dependent phospholipid-binding sites. The encoded protein is a 56-kD antigen recognized by sera from patients with various autoimmune diseases. Several transcript variants encoding two different isoforms have been identified. [provided by RefSeq, Dec 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.2629463).
BS2
High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ANXA11NM_145868.2 linkuse as main transcriptc.1481G>A p.Arg494Gln missense_variant 16/16 ENST00000422982.8 NP_665875.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ANXA11ENST00000422982.8 linkuse as main transcriptc.1481G>A p.Arg494Gln missense_variant 16/161 NM_145868.2 ENSP00000404412 P2P50995-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251102
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135776
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000198
AC:
29
AN:
1461860
Hom.:
0
Cov.:
30
AF XY:
0.0000234
AC XY:
17
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000189
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152196
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis Uncertain:1
Uncertain significance, criteria provided, single submitterresearchDept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital TrustJan 01, 2022- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 26, 2020In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ANXA11-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 494 of the ANXA11 protein (p.Arg494Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.52
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.028
T;T;.;T
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Benign
0.69
D
LIST_S2
Uncertain
0.86
.;.;D;D
M_CAP
Benign
0.0053
T
MetaRNN
Benign
0.26
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;L;.;L
MutationTaster
Benign
0.96
D;D;D;D;D;D;D;D
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-1.9
N;N;D;N
REVEL
Benign
0.19
Sift
Benign
0.042
D;D;D;D
Sift4G
Uncertain
0.051
T;T;T;T
Polyphen
0.99
D;D;.;D
Vest4
0.12
MutPred
0.59
Gain of methylation at K495 (P = 0.0575);Gain of methylation at K495 (P = 0.0575);.;Gain of methylation at K495 (P = 0.0575);
MVP
0.22
MPC
0.094
ClinPred
0.69
D
GERP RS
2.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.15
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
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: rs1318489141; hg19: chr10-81915646; COSMIC: COSV55417492; API