5-170108446-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The ENST00000306268.8(FOXI1):c.972G>C(p.Pro324Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,602,972 control chromosomes in the GnomAD database, including 267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P324P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 15 hom., cov: 33)

Exomes 𝑓: 0.017 ( 252 hom. )

Consequence

FOXI1
ENST00000306268.8 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -2.58

Publications

2 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 5-170108446-G-C is Benign according to our data. Variant chr5-170108446-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 352710.

BP7

Synonymous conserved (PhyloP=-2.58 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.012 (1829/152274) while in subpopulation NFE AF = 0.019 (1291/68016). AF 95% confidence interval is 0.0181. There are 15 homozygotes in GnomAd4. There are 864 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000306268.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXI1	NM_012188.5	MANE Select	c.972G>C	p.Pro324Pro	synonymous	Exon 2 of 2	NP_036320.2
	FOXI1	NM_144769.4		c.687G>C	p.Pro229Pro	synonymous	Exon 2 of 2	NP_658982.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXI1	ENST00000306268.8	TSL:1 MANE Select	c.972G>C	p.Pro324Pro	synonymous	Exon 2 of 2	ENSP00000304286.5
	FOXI1	ENST00000449804.4	TSL:1	c.687G>C	p.Pro229Pro	synonymous	Exon 2 of 2	ENSP00000415483.2

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1829

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00700

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0190

Gnomad OTH

AF:

0.00958

GnomAD2 exomes

AF:

0.0122

AC:

3001

AN:

245174

AF XY:

0.0122

show subpopulations

Gnomad AFR exome

AF:

0.00296

Gnomad AMR exome

AF:

0.00472

Gnomad ASJ exome

AF:

0.00535

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0222

Gnomad NFE exome

AF:

0.0184

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.0167

AC:

24165

AN:

1450698

Hom.:

252

Cov.:

AF XY:

0.0162

AC XY:

11683

AN XY:

719742

show subpopulations

African (AFR)

AF:

0.00273

AC:

AN:

33294

American (AMR)

AF:

0.00526

AC:

233

AN:

44292

Ashkenazi Jewish (ASJ)

AF:

0.00560

AC:

143

AN:

25538

East Asian (EAS)

AF:

0.00

AC:

AN:

39512

South Asian (SAS)

AF:

0.00595

AC:

506

AN:

85098

European-Finnish (FIN)

AF:

0.0227

AC:

1204

AN:

53074

Middle Eastern (MID)

AF:

0.00193

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0192

AC:

21168

AN:

1104396

Other (OTH)

AF:

0.0135

AC:

809

AN:

59786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1365

2730

4096

5461

6826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

804

1608

2412

3216

4020

<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:

0.0120

AC:

1829

AN:

152274

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

864

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00322

AC:

134

AN:

41564

American (AMR)

AF:

0.00699

AC:

107

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00374

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0227

AC:

241

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0190

AC:

1291

AN:

68016

Other (OTH)

AF:

0.00948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

187

280

374

467

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0107

Hom.:

Bravo

AF:

0.0104

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal recessive nonsyndromic hearing loss 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.11

(source)

DANN

Benign

0.42

PhyloP100

-2.6

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over