NM_213599.3:c.41-1G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_213599.3(ANO5):c.41-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.0000854 in 1,463,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

ANO5
NM_213599.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.05

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):

gnathodiaphyseal dysplasia
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive limb-girdle muscular dystrophy type 2L
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
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: Pathogenic. The variant received 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.9, offset of 1, new splice context is: tctttcttatttaatttaAGgga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant 11-22203803-G-A is Pathogenic according to our data. Variant chr11-22203803-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 96685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213599.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ANO5	NM_213599.3	MANE Select	c.41-1G>A	splice_acceptor intron	N/A	NP_998764.1	Q75V66
ANO5	NM_001142649.2		c.41-1G>A	splice_acceptor intron	N/A	NP_001136121.1
ANO5	NM_001410963.1		c.41-1G>A	splice_acceptor intron	N/A	NP_001397892.1	A0A804HL91

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ANO5	ENST00000324559.9	TSL:1 MANE Select	c.41-1G>A	splice_acceptor intron	N/A	ENSP00000315371.9	Q75V66
ANO5	ENST00000682341.1		c.41-1G>A	splice_acceptor intron	N/A	ENSP00000508251.1	A0A804HL91
ANO5	ENST00000684663.1		c.41-1G>A	splice_acceptor intron	N/A	ENSP00000508009.1	A0A804HKP2

Frequencies

GnomAD3 genomes

AF:

0.0000660

AC:

AN:

151598

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.000133

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000123

AC:

AN:

244456

AF XY:

0.0000226

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:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000877

AC:

115

AN:

1312034

Hom.:

Cov.:

AF XY:

0.0000989

AC XY:

AN XY:

657018

show subpopulations

African (AFR)

AF:

0.0000330

AC:

AN:

30290

American (AMR)

AF:

0.00

AC:

AN:

43164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24212

East Asian (EAS)

AF:

0.00

AC:

AN:

38174

South Asian (SAS)

AF:

0.00

AC:

AN:

82480

European-Finnish (FIN)

AF:

0.0000195

AC:

AN:

51236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5362

European-Non Finnish (NFE)

AF:

0.000114

AC:

112

AN:

982386

Other (OTH)

AF:

0.0000183

AC:

AN:

54730

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000660

AC:

AN:

151598

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73988

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41254

American (AMR)

AF:

0.0000657

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67884

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000994

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.00000825

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Autosomal recessive limb-girdle muscular dystrophy type 2L (1)

Gnathodiaphyseal dysplasia;C1969785:Autosomal recessive limb-girdle muscular dystrophy type 2L (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

(source)

DANN

Benign

0.96

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.92

PhyloP100

4.1

GERP RS

4.0

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.86

Position offset: 2

DS_AL_spliceai

0.92

Position offset: 1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over