11-22250927-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_213599.3(ANO5):c.1120-24A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0297 in 1,609,586 control chromosomes in the GnomAD database, including 886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.021 ( 50 hom., cov: 32)

Exomes 𝑓: 0.031 ( 836 hom. )

Consequence

ANO5
NM_213599.3 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.386

Publications

4 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)

ANO5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 11-22250927-A-T is Benign according to our data. Variant chr11-22250927-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0206 (3138/152140) while in subpopulation NFE AF = 0.0339 (2306/67984). AF 95% confidence interval is 0.0328. There are 50 homozygotes in GnomAd4. There are 1457 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 50 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO5	NM_213599.3 link	c.1120-24A>T		intron_variant	Intron 11 of 21	ENST00000324559.9	NP_998764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO5	ENST00000324559.9 link	c.1120-24A>T		intron_variant	Intron 11 of 21	1	NM_213599.3	ENSP00000315371.9

Frequencies

GnomAD3 genomes

AF:

0.0206

AC:

3138

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00727

Gnomad AMI

AF:

0.0703

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0240

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0339

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.0190

AC:

4758

AN:

250078

AF XY:

0.0189

show subpopulations

Gnomad AFR exome

AF:

0.00610

Gnomad AMR exome

AF:

0.00736

Gnomad ASJ exome

AF:

0.00677

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0245

Gnomad NFE exome

AF:

0.0323

Gnomad OTH exome

AF:

0.0197

GnomAD4 exome

AF:

0.0307

AC:

44685

AN:

1457446

Hom.:

836

Cov.:

AF XY:

0.0294

AC XY:

21296

AN XY:

725336

show subpopulations

African (AFR)

AF:

0.00536

AC:

179

AN:

33366

American (AMR)

AF:

0.00812

AC:

363

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00571

AC:

149

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.00157

AC:

135

AN:

86146

European-Finnish (FIN)

AF:

0.0258

AC:

1370

AN:

53180

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0369

AC:

40875

AN:

1108402

Other (OTH)

AF:

0.0266

AC:

1605

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

2497

4993

7490

9986

12483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1566

3132

4698

6264

7830

<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:

0.0206

AC:

3138

AN:

152140

Hom.:

Cov.:

AF XY:

0.0196

AC XY:

1457

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00725

AC:

301

AN:

41530

American (AMR)

AF:

0.0108

AC:

165

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5182

South Asian (SAS)

AF:

0.00166

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0240

AC:

254

AN:

10594

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0339

AC:

2306

AN:

67984

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

160

321

481

642

802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0141

Hom.:

Bravo

AF:

0.0195

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Miyoshi muscular dystrophy 3

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 16, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Gnathodiaphyseal dysplasia

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2L

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.2

(source)

DANN

Benign

0.56

PhyloP100

-0.39

La Branchor

0.48

BranchPoint Hunter

2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over