NM_012188.5:c.574+573T>C

Variant names:

• chr5-170107104-T-C
• rs11951903
• NM_012188.5:c.574+573T>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.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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.61
• Publications: 3 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 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
• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.378 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXI1	NM_012188.5	MANE Select	c.574+573T>C		intron	N/A	NP_036320.2
	FOXI1	NM_144769.4		c.574+573T>C		intron	N/A	NP_658982.1	Q12951-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXI1	ENST00000306268.8	TSL:1 MANE Select	c.574+573T>C		intron	N/A	ENSP00000304286.5	Q12951-1
	FOXI1	ENST00000449804.4	TSL:1	c.574+573T>C		intron	N/A	ENSP00000415483.2	Q12951-2

Frequencies

GnomAD3 genomes AF: 0.0433 AC: 6581 AN: 152126 Hom.: 570 Cov.: 33

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

African (AFR) AF: 0.0854 AC: 450 AN: 5270

American (AMR) AF: 0.0281 AC: 9 AN: 320

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 31 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: 4 AN: 88

Middle Eastern (MID) AF: 0.0247 AC: 14 AN: 566

European-Non Finnish (NFE) AF: 0.00569 AC: 1445 AN: 253780

Other (OTH) AF: 0.0465 AC: 426 AN: 9152

GnomAD4 genome AF: 0.0435 AC: 6615 AN: 152244 Hom.: 577 Cov.: 33 AF XY: 0.0456 AC XY: 3392 AN XY: 74440

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: 86 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: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00666 AC: 453 AN: 68026

Other (OTH) AF: 0.0544 AC: 115 AN: 2114

Alfa AF: 0.0279 Hom.: 24

Bravo AF: 0.0463

Asia WGS AF: 0.221 AC: 765 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.027
DANN	Benign	0.63
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11951903; hg19: chr5-169534108;