Genetic Variant NM_012188.5:c.574+573T>C (chr5-170107104-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_012188.5(FOXI1):c.574+573T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 429,976 control chromosomes in the GnomAD database, including 747 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 0.043 ( 577 hom., cov: 33)

Exomes 𝑓: 0.012 ( 170 hom. )

Consequence

FOXI1
NM_012188.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.61

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=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
FOXI1	NM_012188.5 link	c.574+573T>C	intron_variant	Intron 1 of 1	ENST00000306268.8	NP_036320.2
FOXI1	NM_144769.4 link	c.574+573T>C	intron_variant	Intron 1 of 1		NP_658982.1
FOXI1	XR_941092.2 link	n.780+43T>C	intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXI1	ENST00000306268.8 link	c.574+573T>C		intron_variant	Intron 1 of 1	1	NM_012188.5	ENSP00000304286.5		Q12951-1
FOXI1	ENST00000449804.4 link	c.574+573T>C		intron_variant	Intron 1 of 1	1		ENSP00000415483.2		Q12951-2

Frequencies

GnomAD3 genomes

AF:

0.0433

AC:

6581

AN:

152126

Hom.:

570

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0697

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0300

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.392

Gnomad SAS

AF:

0.0921

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00666

Gnomad OTH

AF:

0.0459

GnomAD4 exome

AF:

0.0120

AC:

3343

AN:

277732

Hom.:

170

AF XY:

0.0111

AC XY:

1464

AN XY:

131794

show subpopulations

African (AFR)

AF:

0.0854

AC:

450

AN:

5270

American (AMR)

AF:

0.0281

AC:

AN:

320

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

AN:

1704

East Asian (EAS)

AF:

0.426

AC:

532

AN:

1250

South Asian (SAS)

AF:

0.0771

AC:

432

AN:

5602

European-Finnish (FIN)

AF:

0.0455

AC:

AN:

Middle Eastern (MID)

AF:

0.0247

AC:

AN:

566

European-Non Finnish (NFE)

AF:

0.00569

AC:

1445

AN:

253780

Other (OTH)

AF:

0.0465

AC:

426

AN:

9152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

158

316

474

632

790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<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:

0.0435

AC:

6615

AN:

152244

Hom.:

577

Cov.:

AF XY:

0.0456

AC XY:

3392

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0699

AC:

2902

AN:

41518

American (AMR)

AF:

0.0301

AC:

460

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

AN:

3472

East Asian (EAS)

AF:

0.392

AC:

2023

AN:

5156

South Asian (SAS)

AF:

0.0922

AC:

445

AN:

4828

European-Finnish (FIN)

AF:

0.0120

AC:

127

AN:

10624

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00666

AC:

453

AN:

68026

Other (OTH)

AF:

0.0544

AC:

115

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

287

574

860

1147

1434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<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:

0.0279

Hom.:

Bravo

AF:

0.0463

Asia WGS

AF:

0.221

AC:

765

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.027

(source)

DANN

Benign

0.63

PhyloP100

-2.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Computational scores

Splicing

Publications

Other links and lift over