chr5-170107541-T-C

Variant names:

• chr5-170107541-T-C
• rs7380481
• NM_012188.5:c.575-508T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012188.5(FOXI1):​c.575-508T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 152,112 control chromosomes in the GnomAD database, including 6,414 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 0.28 (6414 hom., cov: 32)
• Consequence: FOXI1 NM_012188.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.272
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012188.5. 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.575-508T>C		intron	N/A	NP_036320.2
	FOXI1	NM_144769.4		c.575-793T>C		intron	N/A	NP_658982.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXI1	ENST00000306268.8	TSL:1 MANE Select	c.575-508T>C		intron	N/A	ENSP00000304286.5
	FOXI1	ENST00000449804.4	TSL:1	c.575-793T>C		intron	N/A	ENSP00000415483.2

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42087 AN: 151994 Hom.: 6420 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.266

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.277 AC: 42072 AN: 152112 Hom.: 6414 Cov.: 32 AF XY: 0.276 AC XY: 20524 AN XY: 74386

African (AFR) AF: 0.150 AC: 6222 AN: 41506

American (AMR) AF: 0.317 AC: 4845 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1211 AN: 3466

East Asian (EAS) AF: 0.295 AC: 1524 AN: 5164

South Asian (SAS) AF: 0.317 AC: 1524 AN: 4804

European-Finnish (FIN) AF: 0.238 AC: 2521 AN: 10596

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.343 AC: 23299 AN: 67976

Other (OTH) AF: 0.263 AC: 554 AN: 2110

Alfa AF: 0.297 Hom.: 920

Bravo AF: 0.276

Asia WGS AF: 0.285 AC: 988 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.8
DANN	Benign	0.39
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7380481; hg19: chr5-169534545;