rs143777403

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_213599.3(ANO5):c.155A>G(p.Asn52Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00273 in 1,613,408 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 9 hom. )

Consequence

ANO5
NM_213599.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:4

Conservation

PhyloP100: 6.14

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. 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 0 benign, 11 uncertain in NM_213599.3

BP4

Computational evidence support a benign effect (MetaRNN=0.037495136).

BS2

High AC in GnomAd4 at 367 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3 link	c.155A>G	p.Asn52Ser	missense_variant	Exon 4 of 22	ENST00000324559.9	NP_998764.1	Q75V66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9 link	c.155A>G	p.Asn52Ser	missense_variant	Exon 4 of 22	1	NM_213599.3	ENSP00000315371.9		Q75V66

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

367

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00479

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00340

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00215

AC:

541

AN:

251140

AF XY:

0.00220

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00224

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.00287

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00276

AC:

4033

AN:

1461276

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

2020

AN XY:

726940

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

AC:

AN:

33444

Gnomad4 AMR exome

AF:

0.00206

AC:

AN:

44598

Gnomad4 ASJ exome

AF:

0.0000383

AC:

AN:

26112

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39690

Gnomad4 SAS exome

AF:

0.00233

AC:

201

AN:

86252

Gnomad4 FIN exome

AF:

0.00135

AC:

AN:

53366

Gnomad4 NFE exome

AF:

0.00311

AC:

3455

AN:

1111714

Gnomad4 Remaining exome

AF:

0.00277

AC:

167

AN:

60340

Heterozygous variant carriers

241

482

724

965

1206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.00241

AC:

367

AN:

152132

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000843

AC:

0.000842561

AN:

0.000842561

Gnomad4 AMR

AF:

0.00478

AC:

0.00478312

AN:

0.00478312

Gnomad4 ASJ

AF:

0.000288

AC:

0.000288184

AN:

0.000288184

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00207

AC:

0.00207297

AN:

0.00207297

Gnomad4 FIN

AF:

0.000943

AC:

0.000942863

AN:

0.000942863

Gnomad4 NFE

AF:

0.00340

AC:

0.00339876

AN:

0.00339876

Gnomad4 OTH

AF:

0.00331

AC:

0.00331439

AN:

0.00331439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<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:

0.00250

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00190

AC:

231

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:4Benign:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ANO5: PM3:Strong, PM2:Supporting, BP4 -

Aug 31, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 03, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 21, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22980763, 23041008, 26810512, 31931849, 32419263, 25891276, 26911675, 25326637, 23606453, 30564623, 30919934, 31517061) -

Apr 17, 2024

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

not specified

Uncertain:1Benign:1

Jan 01, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ANO5 c.155A>G (p.Asn52Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 251140 control in the gnomAD v2 database, including 2 homozygotes. Additionally, the variant allele was observed predominantly at a frequency of 0.0048 within the Latino subpopulation at in the gnomAD v3 database (genomes data). The observed variant frequency within Latino control individuals in the gnomAD v3 database is over one fold of the estimated maximal expected allele frequency for a pathogenic variant in ANO5 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.0048 vs 0.0047), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.155A>G has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Sarkozy_2012, Sarkozy__2013, Wahbi_2013, Lee_2014, Savarese_2015, Nallamilli_2018, Ten Dam_2019, Mair_2020). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=7), benign (n=1), likely benign (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Gnathodiaphyseal dysplasia

Uncertain:1Benign:1

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 29, 2024

Dr.Nikuei Genetic Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ANO5-Related Muscle Diseases

Uncertain:1

Aug 24, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.060

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.74

M_CAP

Benign

0.077

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.3

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.5

REVEL

Benign

0.17

Sift

Benign

0.15

Sift4G

Benign

0.35

Polyphen

0.98

Vest4

0.83

MVP

0.86

MPC

0.42

ClinPred

0.012

GERP RS

5.9

Varity_R

0.12

gMVP

0.32

Mutation Taster

=69/31

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over