NM_213599.3:c.1042G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate

The NM_213599.3(ANO5):​c.1042G>A​(p.Gly348Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G348C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

5
11
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5

Conservation

PhyloP100: 9.41

Publications

0 publications found
Variant links:
Genes affected
ANO5 (HGNC:27337): (anoctamin 5) This gene encodes a member of the anoctamin family of transmembrane proteins. The encoded protein is likely a calcium activated chloride channel. Mutations in this gene have been associated with gnathodiaphyseal dysplasia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]
ANO5 Gene-Disease associations (from GenCC):
  • autosomal recessive limb-girdle muscular dystrophy
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • gnathodiaphyseal dysplasia
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
  • autosomal recessive limb-girdle muscular dystrophy type 2L
    Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
  • Miyoshi muscular dystrophy 3
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_213599.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-22250769-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1469437.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANO5NM_213599.3 linkc.1042G>A p.Gly348Ser missense_variant Exon 11 of 22 ENST00000324559.9 NP_998764.1 Q75V66

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANO5ENST00000324559.9 linkc.1042G>A p.Gly348Ser missense_variant Exon 11 of 22 1 NM_213599.3 ENSP00000315371.9 Q75V66

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152130
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000279
AC:
7
AN:
251016
AF XY:
0.0000369
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000441
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461744
Hom.:
0
Cov.:
32
AF XY:
0.0000248
AC XY:
18
AN XY:
727176
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33470
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39678
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000261
AC:
29
AN:
1111916
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60388
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
2
4
7
9
11
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152130
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74312
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41414
American (AMR)
AF:
0.00
AC:
0
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000735
AC:
5
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.585
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000225
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Mar 06, 2018
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 02, 2023
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L Pathogenic:1
Nov 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 348 of the ANO5 protein (p.Gly348Ser). This variant is present in population databases (rs139344099, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (internal data). ClinVar contains an entry for this variant (Variation ID: 281308). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ANO5 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Limb-girdle muscular dystrophy, recessive Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

ANO5-Related Muscle Diseases Uncertain:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Miyoshi myopathy Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Uncertain
0.020
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.29
T
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.86
D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Benign
1.5
L
PhyloP100
9.4
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-4.3
D
REVEL
Pathogenic
0.74
Sift
Uncertain
0.024
D
Sift4G
Uncertain
0.023
D
Polyphen
1.0
D
Vest4
0.87
MutPred
0.51
Gain of glycosylation at G348 (P = 0.048);
MVP
0.95
MPC
0.42
ClinPred
0.94
D
GERP RS
5.5
Varity_R
0.57
gMVP
0.87
Mutation Taster
=30/70
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs139344099; hg19: chr11-22272315; API