rs72828668

Positions:

• chr5-170108942-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012188.5(FOXI1):​c.*331G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0221 in 294,548 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (51 hom., cov: 33)
  • Exomes 𝑓: 0.024 (59 hom.)
• Consequence: FOXI1 NM_012188.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.390

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-170108942-G-C is Benign according to our data. Variant chr5-170108942-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 904692.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXI1	NM_012188.5	c.*331G>C		3_prime_UTR_variant	2/2	ENST00000306268.8
FOXI1	NM_144769.4	c.*331G>C		3_prime_UTR_variant	2/2
FOXI1	XR_941092.2	n.1674G>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXI1	ENST00000306268.8	c.*331G>C		3_prime_UTR_variant	2/2	1	NM_012188.5	P1
FOXI1	ENST00000449804.4	c.*331G>C		3_prime_UTR_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3115 AN: 152136 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00427

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.0256

Gnomad EAS AF: 0.0378

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0226

Gnomad OTH AF: 0.0192

GnomAD4 exome AF: 0.0238 AC: 3387 AN: 142294 Hom.: 59 Cov.: 0 AF XY: 0.0250 AC XY: 1838 AN XY: 73630

Gnomad4 AFR exome AF: 0.00556

Gnomad4 AMR exome AF: 0.00838

Gnomad4 ASJ exome AF: 0.0246

Gnomad4 EAS exome AF: 0.0305

Gnomad4 SAS exome AF: 0.0540

Gnomad4 FIN exome AF: 0.0415

Gnomad4 NFE exome AF: 0.0205

Gnomad4 OTH exome AF: 0.0191

GnomAD4 genome AF: 0.0205 AC: 3115 AN: 152254 Hom.: 51 Cov.: 33 AF XY: 0.0224 AC XY: 1665 AN XY: 74424

Gnomad4 AFR AF: 0.00426

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.0256

Gnomad4 EAS AF: 0.0378

Gnomad4 SAS AF: 0.0607

Gnomad4 FIN AF: 0.0503

Gnomad4 NFE AF: 0.0226

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.0195 Hom.: 6

Bravo AF: 0.0156

Asia WGS AF: 0.0310 AC: 110 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.5
DANN	Benign	0.78

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

LitVar

Other links and lift over

dbSNP: rs72828668; hg19: chr5-169535946;