Genetic Variant ANO9:p.Phe705Phe (chr11-418735-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_001012302.3(ANO9):c.2115C>T(p.Phe705Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,612,992 control chromosomes in the GnomAD database, including 422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.017 ( 36 hom., cov: 33)

Exomes 𝑓: 0.020 ( 386 hom. )

Consequence

ANO9
NM_001012302.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.797

Variant links:

Genes affected

ANO9 (HGNC:20679): (anoctamin 9) The protein encoded by this gene is a member of the TMEM16 (anoctamin) family of proteins, some of which form integral membrane calcium-activated chloride channels. The function of the encoded protein has yet to be elucidated, although it may have channel-forming abilities and also may have phospholipid scramblase activity. This gene has been observed to be upregulated in stage II and III colorectal cancers. [provided by RefSeq, Dec 2016]

ANO9 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 11-418735-G-A is Benign according to our data. Variant chr11-418735-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3401267.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.797 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0168 (2563/152304) while in subpopulation AMR AF= 0.0464 (710/15300). AF 95% confidence interval is 0.0436. There are 36 homozygotes in gnomad4. There are 1256 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANO9	NM_001012302.3 link	c.2115C>T	p.Phe705Phe	synonymous_variant	Exon 22 of 23	ENST00000332826.7	NP_001012302.2	A1A5B4-1
ANO9	NM_001347882.2 link	c.1683C>T	p.Phe561Phe	synonymous_variant	Exon 21 of 22		NP_001334811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANO9	ENST00000332826.7 link	c.2115C>T	p.Phe705Phe	synonymous_variant	Exon 22 of 23	1	NM_001012302.3	ENSP00000332788.6		A1A5B4-1

Frequencies

GnomAD3 genomes

AF:

0.0168

AC:

2557

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00519

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0461

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0211

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.0176

AC:

4391

AN:

250174

Hom.:

AF XY:

0.0163

AC XY:

2217

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.00465

Gnomad AMR exome

AF:

0.0423

Gnomad ASJ exome

AF:

0.00680

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00317

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.0204

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0204

AC:

29754

AN:

1460688

Hom.:

386

Cov.:

AF XY:

0.0197

AC XY:

14348

AN XY:

726626

show subpopulations

Gnomad4 AFR exome

AF:

0.00335

Gnomad4 AMR exome

AF:

0.0426

Gnomad4 ASJ exome

AF:

0.00643

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00314

Gnomad4 FIN exome

AF:

0.0129

Gnomad4 NFE exome

AF:

0.0229

Gnomad4 OTH exome

AF:

0.0195

GnomAD4 genome

AF:

0.0168

AC:

2563

AN:

152304

Hom.:

Cov.:

AF XY:

0.0169

AC XY:

1256

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00517

Gnomad4 AMR

AF:

0.0464

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.0121

Gnomad4 NFE

AF:

0.0211

Gnomad4 OTH

AF:

0.0132

Alfa

AF:

0.0177

Hom.:

Bravo

AF:

0.0174

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0189

EpiControl

AF:

0.0174

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 26, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.91

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over