rs6555887

chr5-170109051-G-Achr5-170109051-G-Cchr5-170109051-G-T

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.*440G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.894 in 161,822 control chromosomes in the GnomAD database, including 64,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.89 (60903 hom., cov: 33)
  • Exomes 𝑓: 0.90 (3898 hom.)
• Consequence: FOXI1 NM_012188.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.268

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=-0.87).
• BP6: Variant 5-170109051-G-A is Benign according to our data. Variant chr5-170109051-G-A is described in ClinVar as [Benign]. Clinvar id is 352717.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXI1	NM_012188.5	c.*440G>A		3_prime_UTR_variant	2/2	ENST00000306268.8
FOXI1	NM_144769.4	c.*440G>A		3_prime_UTR_variant	2/2
FOXI1	XR_941092.2	n.1783G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXI1	ENST00000306268.8	c.*440G>A		3_prime_UTR_variant	2/2	1	NM_012188.5	P1
FOXI1	ENST00000449804.4	c.*440G>A		3_prime_UTR_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.894 AC: 136004 AN: 152162 Hom.: 60860 Cov.: 33

Gnomad AFR AF: 0.860

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.908

Gnomad ASJ AF: 0.940

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.932

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.890

GnomAD4 exome AF: 0.903 AC: 8615 AN: 9542 Hom.: 3898 Cov.: 0 AF XY: 0.904 AC XY: 4478 AN XY: 4952

Gnomad4 AFR exome AF: 0.816

Gnomad4 AMR exome AF: 0.902

Gnomad4 ASJ exome AF: 0.939

Gnomad4 EAS exome AF: 0.992

Gnomad4 SAS exome AF: 0.933

Gnomad4 FIN exome AF: 0.877

Gnomad4 NFE exome AF: 0.900

Gnomad4 OTH exome AF: 0.898

GnomAD4 genome AF: 0.894 AC: 136102 AN: 152280 Hom.: 60903 Cov.: 33 AF XY: 0.892 AC XY: 66443 AN XY: 74458

Gnomad4 AFR AF: 0.860

Gnomad4 AMR AF: 0.908

Gnomad4 ASJ AF: 0.940

Gnomad4 EAS AF: 0.986

Gnomad4 SAS AF: 0.931

Gnomad4 FIN AF: 0.864

Gnomad4 NFE AF: 0.905

Gnomad4 OTH AF: 0.891

Alfa AF: 0.902 Hom.: 59583

Bravo AF: 0.895

Asia WGS AF: 0.942 AC: 3274 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.8
Dann	Benign	0.50

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: rs6555887; hg19: chr5-169536055;