2-69804572-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001153.5(ANXA4):​c.137G>A​(p.Arg46His) variant causes a missense change. The variant allele was found at a frequency of 0.000088 in 1,613,682 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000084 ( 1 hom. )

Consequence

ANXA4
NM_001153.5 missense

Scores

5
4
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.27
Variant links:
Genes affected
ANXA4 (HGNC:542): (annexin A4) Annexin IV (ANX4) belongs to the annexin family of calcium-dependent phospholipid binding proteins. Although their functions are still not clearly defined, several members of the annexin family have been implicated in membrane-related events along exocytotic and endocytotic pathways. ANX4 has 45 to 59% identity with other members of its family and shares a similar size and exon-intron organization. Isolated from human placenta, ANX4 encodes a protein that has possible interactions with ATP, and has in vitro anticoagulant activity and also inhibits phospholipase A2 activity. ANX4 is almost exclusively expressed in epithelial cells. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09482783).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ANXA4NM_001153.5 linkuse as main transcriptc.137G>A p.Arg46His missense_variant 4/13 ENST00000394295.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ANXA4ENST00000394295.6 linkuse as main transcriptc.137G>A p.Arg46His missense_variant 4/131 NM_001153.5 P1P09525-3

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152080
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00346
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000176
AC:
44
AN:
250416
Hom.:
1
AF XY:
0.000148
AC XY:
20
AN XY:
135372
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00259
Gnomad EAS exome
AF:
0.000382
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000442
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000842
AC:
123
AN:
1461602
Hom.:
1
Cov.:
31
AF XY:
0.0000784
AC XY:
57
AN XY:
727092
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00276
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000189
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152080
Hom.:
0
Cov.:
31
AF XY:
0.0000942
AC XY:
7
AN XY:
74300
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00346
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000135
Hom.:
0
Bravo
AF:
0.000136
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000140
AC:
17
EpiCase
AF:
0.00
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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 12, 2023The c.137G>A (p.R46H) alteration is located in exon 4 (coding exon 3) of the ANXA4 gene. This alteration results from a G to A substitution at nucleotide position 137, causing the arginine (R) at amino acid position 46 to be replaced by a histidine (H). 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
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.043
.;T
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.095
T;T
MetaSVM
Benign
-0.85
T
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-4.3
D;D
REVEL
Uncertain
0.34
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.57
MVP
0.70
MPC
0.96
ClinPred
0.45
T
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.85

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.

Other links and lift over

dbSNP: rs377447418; hg19: chr2-70031704; API