Genetic Variant NM_012188.5:c.574+71T>C (chr5-170106602-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_012188.5(FOXI1):c.574+71T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 1,587,342 control chromosomes in the GnomAD database, including 85,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.27 ( 6281 hom., cov: 33)

Exomes 𝑓: 0.33 ( 79555 hom. )

Consequence

FOXI1
NM_012188.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0800

Publications

8 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=-0.76).

BP6

Variant 5-170106602-T-C is Benign according to our data. Variant chr5-170106602-T-C is described in ClinVar as Benign. ClinVar VariationId is 1297806.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
FOXI1	NM_012188.5 link	c.574+71T>C	intron_variant	Intron 1 of 1	ENST00000306268.8	NP_036320.2
FOXI1	NM_144769.4 link	c.574+71T>C	intron_variant	Intron 1 of 1		NP_658982.1
FOXI1	XR_941092.2 link	n.635+71T>C	intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXI1	ENST00000306268.8 link	c.574+71T>C		intron_variant	Intron 1 of 1	1	NM_012188.5	ENSP00000304286.5		Q12951-1
FOXI1	ENST00000449804.4 link	c.574+71T>C		intron_variant	Intron 1 of 1	1		ENSP00000415483.2		Q12951-2

Frequencies

GnomAD3 genomes

AF:

0.273

AC:

41503

AN:

152064

Hom.:

6287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.323

Gnomad AMR

AF:

0.314

Gnomad ASJ

AF:

0.346

Gnomad EAS

AF:

0.295

Gnomad SAS

AF:

0.318

Gnomad FIN

AF:

0.239

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.341

Gnomad OTH

AF:

0.260

GnomAD4 exome

AF:

0.331

AC:

474375

AN:

1435160

Hom.:

79555

AF XY:

0.331

AC XY:

235681

AN XY:

712230

show subpopulations

African (AFR)

AF:

0.134

AC:

4385

AN:

32706

American (AMR)

AF:

0.295

AC:

11898

AN:

40270

Ashkenazi Jewish (ASJ)

AF:

0.347

AC:

8876

AN:

25588

East Asian (EAS)

AF:

0.302

AC:

11562

AN:

38324

South Asian (SAS)

AF:

0.335

AC:

28053

AN:

83634

European-Finnish (FIN)

AF:

0.244

AC:

12557

AN:

51466

Middle Eastern (MID)

AF:

0.277

AC:

1591

AN:

5738

European-Non Finnish (NFE)

AF:

0.343

AC:

376407

AN:

1097944

Other (OTH)

AF:

0.320

AC:

19046

AN:

59490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

18771

37542

56313

75084

93855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12084

24168

36252

48336

60420

<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:

0.273

AC:

41487

AN:

152182

Hom.:

6281

Cov.:

AF XY:

0.272

AC XY:

20242

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.140

AC:

5808

AN:

41532

American (AMR)

AF:

0.314

AC:

4809

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.346

AC:

1200

AN:

3470

East Asian (EAS)

AF:

0.295

AC:

1522

AN:

5164

South Asian (SAS)

AF:

0.317

AC:

1527

AN:

4818

European-Finnish (FIN)

AF:

0.239

AC:

2532

AN:

10612

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.341

AC:

23183

AN:

67964

Other (OTH)

AF:

0.257

AC:

543

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1562

3123

4685

6246

7808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

418

836

1254

1672

2090

<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:

0.332

Hom.:

6926

Bravo

AF:

0.272

Asia WGS

AF:

0.283

AC:

980

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.6

(source)

DANN

Benign

0.85

PhyloP100

-0.080

Mutation Taster

=100/0

polymorphism (auto)

(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