5-170108942-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012188.5(FOXI1):c.*331G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 294,548 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.020 ( 51 hom., cov: 33)

Exomes 𝑓: 0.024 ( 59 hom. )

Consequence

FOXI1
NM_012188.5 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.390

Publications

3 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
FOXI1	NM_012188.5 link	c.*331G>C	3_prime_UTR_variant	Exon 2 of 2	ENST00000306268.8	NP_036320.2
FOXI1	XR_941092.2 link	n.1674G>C	non_coding_transcript_exon_variant	Exon 3 of 3
FOXI1	NM_144769.4 link	c.*331G>C	3_prime_UTR_variant	Exon 2 of 2		NP_658982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXI1	ENST00000306268.8 link	c.*331G>C		3_prime_UTR_variant	Exon 2 of 2	1	NM_012188.5	ENSP00000304286.5		Q12951-1
FOXI1	ENST00000449804.4 link	c.*331G>C		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000415483.2		Q12951-2

Frequencies

GnomAD3 genomes

AF:

0.0205

AC:

3115

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00427

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0150

Gnomad ASJ

AF:

0.0256

Gnomad EAS

AF:

0.0378

Gnomad SAS

AF:

0.0602

Gnomad FIN

AF:

0.0503

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0226

Gnomad OTH

AF:

0.0192

GnomAD4 exome

AF:

0.0238

AC:

3387

AN:

142294

Hom.:

Cov.:

AF XY:

0.0250

AC XY:

1838

AN XY:

73630

show subpopulations

African (AFR)

AF:

0.00556

AC:

AN:

5036

American (AMR)

AF:

0.00838

AC:

AN:

6208

Ashkenazi Jewish (ASJ)

AF:

0.0246

AC:

118

AN:

4800

East Asian (EAS)

AF:

0.0305

AC:

286

AN:

9382

South Asian (SAS)

AF:

0.0540

AC:

553

AN:

10244

European-Finnish (FIN)

AF:

0.0415

AC:

336

AN:

8098

Middle Eastern (MID)

AF:

0.0281

AC:

AN:

712

European-Non Finnish (NFE)

AF:

0.0205

AC:

1826

AN:

89002

Other (OTH)

AF:

0.0191

AC:

168

AN:

8812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

160

320

481

641

801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.0205

AC:

3115

AN:

152254

Hom.:

Cov.:

AF XY:

0.0224

AC XY:

1665

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00426

AC:

177

AN:

41556

American (AMR)

AF:

0.0150

AC:

229

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0256

AC:

AN:

3472

East Asian (EAS)

AF:

0.0378

AC:

196

AN:

5180

South Asian (SAS)

AF:

0.0607

AC:

292

AN:

4814

European-Finnish (FIN)

AF:

0.0503

AC:

533

AN:

10588

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0226

AC:

1536

AN:

68018

Other (OTH)

AF:

0.0190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

168

336

505

673

841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0195

Hom.:

Bravo

AF:

0.0156

Asia WGS

AF:

0.0310

AC:

110

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.5

(source)

DANN

Benign

0.78

PhyloP100

0.39

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