5-170109541-C-CTT

Variant names:

• chr5-170109541-C-CTT
• rs3839285
• NM_012188.5:c.*937_*938dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012188.5(FOXI1):​c.*937_*938dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000462 in 151,666 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXI1 NM_012188.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.211
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.*937_*938dupTT		3_prime_UTR	Exon 2 of 2	NP_036320.2
	FOXI1	NM_144769.4		c.*937_*938dupTT		3_prime_UTR	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.*937_*938dupTT		3_prime_UTR	Exon 2 of 2	ENSP00000304286.5
	FOXI1	ENST00000449804.4	TSL:1	c.*937_*938dupTT		3_prime_UTR	Exon 2 of 2	ENSP00000415483.2

Frequencies

GnomAD3 genomes AF: 0.0000462 AC: 7 AN: 151666 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 12

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0000462 AC: 7 AN: 151666 Hom.: 0 Cov.: 22 AF XY: 0.0000405 AC XY: 3 AN XY: 74054

African (AFR) AF: 0.0000970 AC: 4 AN: 41224

American (AMR) AF: 0.0000656 AC: 1 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67956

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 96

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.21

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3839285; hg19: chr5-169536545;