Genetic Variant ANO4:p.Ser107Leu (chr12-100942399-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2BP4_StrongBS1BS2

The NM_001286615.2(ANO4):c.320C>T(p.Ser107Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

ANO4
NM_001286615.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46

Publications

1 publications found

Variant links:

Genes affected

ANO4 (HGNC:23837): (anoctamin 4) Enables intracellular calcium activated chloride channel activity. Involved in chloride transport. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ANO4 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ANO4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.5332 (below the threshold of 3.09). Trascript score misZ: 3.1552 (above the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder.

BP4

Computational evidence support a benign effect (MetaRNN=0.043947548).

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000411 (60/1461588) while in subpopulation AMR AF = 0.0000672 (3/44676). AF 95% confidence interval is 0.0000212. There are 0 homozygotes in GnomAdExome4. There are 30 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286615.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANO4	NM_001286615.2	MANE Select	c.320C>T	p.Ser107Leu	missense	Exon 5 of 28	NP_001273544.1	Q32M45-1
ANO4	NM_001286616.1		c.320C>T	p.Ser107Leu	missense	Exon 4 of 27	NP_001273545.1	Q32M45-1
ANO4	NM_178826.4		c.215C>T	p.Ser72Leu	missense	Exon 4 of 27	NP_849148.2	Q32M45-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANO4	ENST00000392977.8	TSL:2 MANE Select	c.320C>T	p.Ser107Leu	missense	Exon 5 of 28	ENSP00000376703.3	Q32M45-1
ANO4	ENST00000644049.1		c.818C>T	p.Ser273Leu	missense	Exon 7 of 30	ENSP00000494481.1	A0A2R8Y532
ANO4	ENST00000852684.1		c.320C>T	p.Ser107Leu	missense	Exon 5 of 28	ENSP00000522743.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000558

AC:

AN:

250920

AF XY:

0.0000664

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1461588

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.0000672

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.000651

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111896

Other (OTH)

AF:

0.0000994

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.0000329

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000135

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.070

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.64

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.81

M_CAP

Benign

0.019

MetaRNN

Benign

0.044

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

1.5

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.2

REVEL

Benign

0.020

Sift

Benign

0.50

Sift4G

Benign

0.43

Polyphen

0.23

Vest4

0.19

MVP

0.043

MPC

0.53

ClinPred

0.28

GERP RS

1.7

Varity_R

0.047

gMVP

0.22

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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