rs10063424

Positions:

• chr5-170108518-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012188.5(FOXI1):​c.1044T>C​(p.Tyr348=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,609,276 control chromosomes in the GnomAD database, including 667,570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (62367 hom., cov: 32)
  • Exomes 𝑓: 0.91 (605203 hom.)
• Consequence: FOXI1 NM_012188.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.667

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=-0.81).
• BP6: Variant 5-170108518-T-C is Benign according to our data. Variant chr5-170108518-T-C is described in ClinVar as [Benign]. Clinvar id is 260212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-170108518-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.667 with no splicing effect.
• 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	Protein	UniProt
FOXI1	NM_012188.5	c.1044T>C	p.Tyr348=	synonymous_variant	2/2	ENST00000306268.8	NP_036320.2
FOXI1	NM_144769.4	c.759T>C	p.Tyr253=	synonymous_variant	2/2		NP_658982.1
FOXI1	XR_941092.2	n.1250T>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXI1	ENST00000306268.8	c.1044T>C	p.Tyr348=	synonymous_variant	2/2	1	NM_012188.5	ENSP00000304286	P1
FOXI1	ENST00000449804.4	c.759T>C	p.Tyr253=	synonymous_variant	2/2	1		ENSP00000415483

Frequencies

GnomAD3 genomes AF: 0.905 AC: 137631 AN: 152150 Hom.: 62314 Cov.: 32

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.912

Gnomad ASJ AF: 0.940

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.931

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.882

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.900

GnomAD3 exomes AF: 0.911 AC: 225284 AN: 247330 Hom.: 102756 AF XY: 0.911 AC XY: 121847 AN XY: 133698

Gnomad AFR exome AF: 0.898

Gnomad AMR exome AF: 0.916

Gnomad ASJ exome AF: 0.934

Gnomad EAS exome AF: 0.987

Gnomad SAS exome AF: 0.934

Gnomad FIN exome AF: 0.862

Gnomad NFE exome AF: 0.901

Gnomad OTH exome AF: 0.900

GnomAD4 exome AF: 0.911 AC: 1327583 AN: 1457008 Hom.: 605203 Cov.: 51 AF XY: 0.912 AC XY: 660125 AN XY: 724206

Gnomad4 AFR exome AF: 0.898

Gnomad4 AMR exome AF: 0.914

Gnomad4 ASJ exome AF: 0.932

Gnomad4 EAS exome AF: 0.987

Gnomad4 SAS exome AF: 0.932

Gnomad4 FIN exome AF: 0.862

Gnomad4 NFE exome AF: 0.909

Gnomad4 OTH exome AF: 0.908

GnomAD4 genome AF: 0.905 AC: 137741 AN: 152268 Hom.: 62367 Cov.: 32 AF XY: 0.903 AC XY: 67236 AN XY: 74436

Gnomad4 AFR AF: 0.897

Gnomad4 AMR AF: 0.913

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: 0.902

Alfa AF: 0.906 Hom.: 101031

Bravo AF: 0.907

Asia WGS AF: 0.944 AC: 3281 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive nonsyndromic hearing loss 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.020
DANN	Benign	0.18

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: rs10063424; hg19: chr5-169535522;