rs2277944

Positions:

• chr5-170106236-G-A

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.279G>A​(p.Arg93=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,577,604 control chromosomes in the GnomAD database, including 36,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (8264 hom., cov: 32)
  • Exomes 𝑓: 0.18 (28604 hom.)
• Consequence: FOXI1 NM_012188.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.39

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=-0.5).
• BP6: Variant 5-170106236-G-A is Benign according to our data. Variant chr5-170106236-G-A is described in ClinVar as [Benign]. Clinvar id is 352702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-170106236-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOXI1	NM_012188.5	c.279G>A	p.Arg93=	synonymous_variant	1/2	ENST00000306268.8	NP_036320.2
FOXI1	NM_144769.4	c.279G>A	p.Arg93=	synonymous_variant	1/2		NP_658982.1
FOXI1	XR_941092.2	n.340G>A		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXI1	ENST00000306268.8	c.279G>A	p.Arg93=	synonymous_variant	1/2	1	NM_012188.5	ENSP00000304286	P1
FOXI1	ENST00000449804.4	c.279G>A	p.Arg93=	synonymous_variant	1/2	1		ENSP00000415483

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43513 AN: 151974 Hom.: 8239 Cov.: 32

Gnomad AFR AF: 0.532

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.271

GnomAD3 exomes AF: 0.231 AC: 43364 AN: 187600 Hom.: 6174 AF XY: 0.224 AC XY: 22614 AN XY: 101130

Gnomad AFR exome AF: 0.550

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.476

Gnomad SAS exome AF: 0.226

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.203

GnomAD4 exome AF: 0.184 AC: 262761 AN: 1425512 Hom.: 28604 Cov.: 35 AF XY: 0.185 AC XY: 130440 AN XY: 706096

Gnomad4 AFR exome AF: 0.551

Gnomad4 AMR exome AF: 0.219

Gnomad4 ASJ exome AF: 0.186

Gnomad4 EAS exome AF: 0.458

Gnomad4 SAS exome AF: 0.222

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.206

GnomAD4 genome AF: 0.287 AC: 43587 AN: 152092 Hom.: 8264 Cov.: 32 AF XY: 0.287 AC XY: 21336 AN XY: 74364

Gnomad4 AFR AF: 0.532

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.245

Gnomad4 FIN AF: 0.195

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.277

Alfa AF: 0.200 Hom.: 1951

Bravo AF: 0.300

Asia WGS AF: 0.347 AC: 1206 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	-	- -

not provided Benign:2

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

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	-0.50
CADD	Benign	4.2
DANN	Benign	0.34

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: rs2277944; hg19: chr5-169533240; COSMIC: COSV60387898;