rs55685928

Positions:

• chr5-170108488-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_012188.5(FOXI1):​c.1014G>A​(p.Ala338=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,601,568 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (13 hom.)
• Consequence: FOXI1 NM_012188.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.07

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 5-170108488-G-A is Benign according to our data. Variant chr5-170108488-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 768050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-170108488-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00787 (1198/152274) while in subpopulation AFR AF= 0.0222 (921/41550). AF 95% confidence interval is 0.021. There are 14 homozygotes in gnomad4. There are 585 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXI1	NM_012188.5	c.1014G>A	p.Ala338=	synonymous_variant	2/2	ENST00000306268.8
FOXI1	NM_144769.4	c.729G>A	p.Ala243=	synonymous_variant	2/2
FOXI1	XR_941092.2	n.1220G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXI1	ENST00000306268.8	c.1014G>A	p.Ala338=	synonymous_variant	2/2	1	NM_012188.5	P1
FOXI1	ENST00000449804.4	c.729G>A	p.Ala243=	synonymous_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.00787 AC: 1198 AN: 152156 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00384 AC: 930 AN: 242238 Hom.: 3 AF XY: 0.00357 AC XY: 466 AN XY: 130598

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.00265

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00299

Gnomad FIN exome AF: 0.0000477

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.00323

GnomAD4 exome AF: 0.00238 AC: 3456 AN: 1449294 Hom.: 13 Cov.: 34 AF XY: 0.00243 AC XY: 1745 AN XY: 719064

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.00276

Gnomad4 ASJ exome AF: 0.00898

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00283

Gnomad4 FIN exome AF: 0.0000567

Gnomad4 NFE exome AF: 0.00164

Gnomad4 OTH exome AF: 0.00440

GnomAD4 genome AF: 0.00787 AC: 1198 AN: 152274 Hom.: 14 Cov.: 33 AF XY: 0.00786 AC XY: 585 AN XY: 74442

Gnomad4 AFR AF: 0.0222

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00533 Hom.: 1

Bravo AF: 0.00833

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 04, 2019	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

FOXI1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal recessive nonsyndromic hearing loss 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.0
DANN	Benign	0.39

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: rs55685928; hg19: chr5-169535492; COSMIC: COSV60389931;