chr10-80157642-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_145868.2(ANXA11):​c.1457C>T​(p.Ser486Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000434 in 1,612,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

ANXA11
NM_145868.2 missense, splice_region

Scores

1
7
11
Splicing: ADA: 0.9867
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.10
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 -4 ACMG points.

BS2
High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ANXA11NM_145868.2 linkuse as main transcriptc.1457C>T p.Ser486Leu missense_variant, splice_region_variant 15/16 ENST00000422982.8 NP_665875.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ANXA11ENST00000422982.8 linkuse as main transcriptc.1457C>T p.Ser486Leu missense_variant, splice_region_variant 15/161 NM_145868.2 ENSP00000404412 P2P50995-1

Frequencies

GnomAD3 genomes
AF:
0.000191
AC:
29
AN:
152054
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00164
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.0000719
AC:
18
AN:
250462
Hom.:
0
AF XY:
0.0000517
AC XY:
7
AN XY:
135370
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000435
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000281
AC:
41
AN:
1460908
Hom.:
0
Cov.:
32
AF XY:
0.0000234
AC XY:
17
AN XY:
726660
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000627
Gnomad4 ASJ exome
AF:
0.0000384
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.000191
AC:
29
AN:
152054
Hom.:
0
Cov.:
32
AF XY:
0.000269
AC XY:
20
AN XY:
74254
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00164
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000955
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.000185
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

ANXA11-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 15, 2023The ANXA11 c.1457C>T variant is predicted to result in the amino acid substitution p.Ser486Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.045% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-81917398-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 09, 2023The c.1457C>T (p.S486L) alteration is located in exon 14 (coding exon 13) of the ANXA11 gene. This alteration results from a C to T substitution at nucleotide position 1457, causing the serine (S) at amino acid position 486 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2023In 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1366578). This variant has not been reported in the literature in individuals affected with ANXA11-related conditions. This variant is present in population databases (rs778082972, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 486 of the ANXA11 protein (p.Ser486Leu). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.51
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.059
T;T;.;T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.91
.;.;D;D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.18
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
L;L;.;L
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-3.2
D;D;.;D
REVEL
Benign
0.10
Sift
Uncertain
0.0080
D;D;.;D
Sift4G
Uncertain
0.049
D;D;T;D
Polyphen
0.98
D;D;.;D
Vest4
0.21
MutPred
0.31
Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);.;Loss of disorder (P = 0.0138);
MVP
0.35
MPC
0.19
ClinPred
0.40
T
GERP RS
4.9
Varity_R
0.22
gMVP
0.31

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.86
SpliceAI score (max)
0.060
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: rs778082972; hg19: chr10-81917398; COSMIC: COSV55417162; API