5-170108488-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_012188.5(FOXI1):c.1014G>A(p.Ala338Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,601,568 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 13 hom. )

Consequence

FOXI1
NM_012188.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.07

Publications

1 publications found

Variant links:

Genes affected

FOXI1 (HGNC:3815): (forkhead box I1) This gene belongs to the forkhead family of transcription factors, which is characterized by a distinct forkhead domain. This gene may play an important role in the development of the cochlea and vestibulum, as well as in embryogenesis. The encoded protein has been found to be required for the transcription of four subunits of a proton pump found in the inner ear, the kidney, and the epididymis. Mutations in this gene have been associated with deafness, autosomal recessive 4. [provided by RefSeq, Jan 2017]

FOXI1 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 4
Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
autosomal recessive distal renal tubular acidosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Pendred syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss disorder
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
enlarged vestibular aqueduct syndrome
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

FOXI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 5-170108488-G-A is Benign according to our data. Variant chr5-170108488-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 768050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.07 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00787 (1198/152274) while in subpopulation AFR AF = 0.0222 (921/41550). AF 95% confidence interval is 0.021. There are 14 homozygotes in GnomAd4. There are 585 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
FOXI1	NM_012188.5 link	c.1014G>A	p.Ala338Ala	synonymous_variant	Exon 2 of 2	ENST00000306268.8	NP_036320.2
FOXI1	NM_144769.4 link	c.729G>A	p.Ala243Ala	synonymous_variant	Exon 2 of 2		NP_658982.1
FOXI1	XR_941092.2 link	n.1220G>A		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXI1	ENST00000306268.8 link	c.1014G>A	p.Ala338Ala	synonymous_variant	Exon 2 of 2	1	NM_012188.5	ENSP00000304286.5		Q12951-1
FOXI1	ENST00000449804.4 link	c.729G>A	p.Ala243Ala	synonymous_variant	Exon 2 of 2	1		ENSP00000415483.2		Q12951-2

Frequencies

GnomAD3 genomes

AF:

0.00787

AC:

1198

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00238

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00384

AC:

930

AN:

242238

AF XY:

0.00357

show subpopulations

Gnomad AFR exome

AF:

0.0219

Gnomad AMR exome

AF:

0.00265

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000477

Gnomad NFE exome

AF:

0.00265

Gnomad OTH exome

AF:

0.00323

GnomAD4 exome

AF:

0.00238

AC:

3456

AN:

1449294

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

1745

AN XY:

719064

show subpopulations

African (AFR)

AF:

0.0214

AC:

712

AN:

33290

American (AMR)

AF:

0.00276

AC:

122

AN:

44188

Ashkenazi Jewish (ASJ)

AF:

0.00898

AC:

227

AN:

25280

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39516

South Asian (SAS)

AF:

0.00283

AC:

239

AN:

84518

European-Finnish (FIN)

AF:

0.0000567

AC:

AN:

52944

Middle Eastern (MID)

AF:

0.0131

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00164

AC:

1814

AN:

1104012

Other (OTH)

AF:

0.00440

AC:

263

AN:

59840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

206

411

617

822

1028

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.00787

AC:

1198

AN:

152274

Hom.:

Cov.:

AF XY:

0.00786

AC XY:

585

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0222

AC:

921

AN:

41550

American (AMR)

AF:

0.00373

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00835

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00166

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00238

AC:

162

AN:

68020

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

112

169

225

281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00499

Hom.:

Bravo

AF:

0.00833

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 07, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 04, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

FOXI1-related disorder

Benign:1

May 13, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal recessive nonsyndromic hearing loss 4

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.0

(source)

DANN

Benign

0.39

PhyloP100

1.1

Mutation Taster

=100/0

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

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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