NM_001286615.2:c.383C>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2

The NM_001286615.2(ANO4):c.383C>A(p.Ser128Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,613,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

ANO4
NM_001286615.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.01

Publications

3 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: Likely_benign. The variant received -6 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=0.22316977).

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000452 (66/1461792) while in subpopulation AMR AF = 0.000179 (8/44716). AF 95% confidence interval is 0.0000886. There are 0 homozygotes in GnomAdExome4. There are 27 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO4	NM_001286615.2 link	c.383C>A	p.Ser128Tyr	missense_variant	Exon 5 of 28	ENST00000392977.8	NP_001273544.1	Q32M45-1B7Z9Z0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ANO4	ENST00000392977.8 link	c.383C>A	p.Ser128Tyr	missense_variant	Exon 5 of 28	2	NM_001286615.2	ENSP00000376703.3	Q32M45-1
ANO4	ENST00000644049.1 link	c.881C>A	p.Ser294Tyr	missense_variant	Exon 7 of 30			ENSP00000494481.1	A0A2R8Y532
ANO4	ENST00000392979.7 link	c.278C>A	p.Ser93Tyr	missense_variant	Exon 4 of 27	2		ENSP00000376705.3	Q32M45-2
ANO4	ENST00000549155.6 link	n.881C>A		non_coding_transcript_exon_variant	Exon 7 of 11	2		ENSP00000449116.2	F8VW62

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000518

AC:

AN:

250994

AF XY:

0.0000516

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.000179

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000342

AC:

AN:

1111966

Other (OTH)

AF:

0.0000828

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41390

American (AMR)

AF:

0.0000655

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 04, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.278C>A (p.S93Y) alteration is located in exon 4 (coding exon 3) of the ANO4 gene. This alteration results from a C to A substitution at nucleotide position 278, causing the serine (S) at amino acid position 93 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

.;.;T

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.1

.;.;L

PhyloP100

7.0

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.7

.;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.010

.;D;D

Sift4G

Benign

0.092

.;T;T

Polyphen

0.97, 0.94

.;D;P

Vest4

0.42, 0.42

MutPred

0.37

.;.;Gain of solvent accessibility (P = 0.039);

MVP

0.068

MPC

1.5

ClinPred

0.38

GERP RS

5.6

Varity_R

0.30

gMVP

0.31

Mutation Taster

=45/55

disease causing

(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

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NM_001286615.2:c.383C>A

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