rs373885901

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.169G>A(p.Asp57Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,612,946 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 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

ANO4
NM_001286615.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.74

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=0.23308668).

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000301 (44/1460812) while in subpopulation AFR AF = 0.0000598 (2/33452). AF 95% confidence interval is 0.0000271. There are 0 homozygotes in GnomAdExome4. There are 25 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO4	NM_001286615.2 link	c.169G>A	p.Asp57Asn	missense_variant	Exon 4 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.169G>A	p.Asp57Asn	missense_variant	Exon 4 of 28	2	NM_001286615.2	ENSP00000376703.3	Q32M45-1
ANO4	ENST00000644049.1 link	c.667G>A	p.Asp223Asn	missense_variant	Exon 6 of 30			ENSP00000494481.1	A0A2R8Y532
ANO4	ENST00000392979.7 link	c.64G>A	p.Asp22Asn	missense_variant	Exon 3 of 27	2		ENSP00000376705.3	Q32M45-2
ANO4	ENST00000549155.6 link	n.667G>A		non_coding_transcript_exon_variant	Exon 6 of 11	2		ENSP00000449116.2	F8VW62

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250848

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1460812

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726680

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000360

AC:

AN:

1111280

Other (OTH)

AF:

0.0000331

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000966

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.64G>A (p.D22N) alteration is located in exon 3 (coding exon 2) of the ANO4 gene. This alteration results from a G to A substitution at nucleotide position 64, causing the aspartic acid (D) at amino acid position 22 to be replaced by an asparagine (N). 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

0.28

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.49

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.058

.;.;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.6

.;.;L

PhyloP100

7.7

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.54

.;N;N

REVEL

Benign

0.11

Sift

Benign

0.056

.;T;T

Sift4G

Benign

0.32

.;T;T

Polyphen

0.73, 0.99

.;P;D

Vest4

0.74

MVP

0.093

MPC

0.52

ClinPred

0.23

GERP RS

5.5

Varity_R

0.22

gMVP

0.48

Mutation Taster

=264/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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.

rs373885901

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