5-170109541-CT-CTT

Variant names:

• chr5-170109541-C-CT
• rs3839285
• NM_012188.5:c.*938dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_012188.5(FOXI1):​c.*938dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 151,692 control chromosomes in the GnomAD database, including 7,789 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (7789 hom., cov: 22)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: FOXI1 NM_012188.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 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 -10 ACMG points.

• BP6: Variant 5-170109541-C-CT is Benign according to our data. Variant chr5-170109541-C-CT is described in ClinVar as Likely_benign. ClinVar VariationId is 352722.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.508 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.*938dupT		3_prime_UTR	Exon 2 of 2	NP_036320.2
	FOXI1	NM_144769.4		c.*938dupT		3_prime_UTR	Exon 2 of 2	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.*938dupT		3_prime_UTR	Exon 2 of 2	ENSP00000304286.5	Q12951-1
	FOXI1	ENST00000449804.4	TSL:1	c.*938dupT		3_prime_UTR	Exon 2 of 2	ENSP00000415483.2	Q12951-2

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42510 AN: 151562 Hom.: 7765 Cov.: 22

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.169

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.167 AC: 2 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.125 AC XY: 1 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: 0.167 AC: 2 AN: 12

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.281 AC: 42583 AN: 151680 Hom.: 7789 Cov.: 22 AF XY: 0.281 AC XY: 20853 AN XY: 74128

African (AFR) AF: 0.514 AC: 21213 AN: 41290

American (AMR) AF: 0.223 AC: 3406 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 667 AN: 3468

East Asian (EAS) AF: 0.471 AC: 2411 AN: 5122

South Asian (SAS) AF: 0.233 AC: 1118 AN: 4792

European-Finnish (FIN) AF: 0.195 AC: 2051 AN: 10528

Middle Eastern (MID) AF: 0.158 AC: 46 AN: 292

European-Non Finnish (NFE) AF: 0.161 AC: 10938 AN: 67930

Other (OTH) AF: 0.273 AC: 573 AN: 2102

Alfa AF: 0.0762 Hom.: 96

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Nonsyndromic Hearing Loss, Mixed (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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;