rs6873124

Variant names:

• chr5-170108730-C-A
• rs6873124
• NM_012188.5:c.*119C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-170108730-C-A
• chr5-170108730-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012188.5(FOXI1):​c.*119C>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 0.218 in 791,022 control chromosomes in the GnomAD database, including 23,562 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7855 hom., cov: 32)
  • Exomes 𝑓: 0.20 (15707 hom.)
• Consequence: FOXI1 NM_012188.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.636
• Publications: 10 publications found

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]

FOXI1 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• autosomal recessive distal renal tubular acidosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Pendred syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss disorder

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• enlarged vestibular aqueduct syndrome

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-170108730-C-A is Benign according to our data. Variant chr5-170108730-C-A is described in ClinVar as Benign. ClinVar VariationId is 352713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXI1	NM_012188.5	c.*119C>A		3_prime_UTR_variant	Exon 2 of 2	ENST00000306268.8	NP_036320.2
FOXI1	XR_941092.2	n.1462C>A		non_coding_transcript_exon_variant	Exon 3 of 3
FOXI1	NM_144769.4	c.*119C>A		3_prime_UTR_variant	Exon 2 of 2		NP_658982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXI1	ENST00000306268.8	c.*119C>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_012188.5	ENSP00000304286.5
FOXI1	ENST00000449804.4	c.*119C>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000415483.2

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42729 AN: 151986 Hom.: 7831 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.473

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.203 AC: 129781 AN: 638918 Hom.: 15707 Cov.: 8 AF XY: 0.201 AC XY: 69270 AN XY: 343906

African (AFR) AF: 0.518 AC: 9065 AN: 17510

American (AMR) AF: 0.220 AC: 8020 AN: 36414

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 3632 AN: 19328

East Asian (EAS) AF: 0.459 AC: 15769 AN: 34360

South Asian (SAS) AF: 0.214 AC: 13904 AN: 64836

European-Finnish (FIN) AF: 0.189 AC: 8320 AN: 44050

Middle Eastern (MID) AF: 0.174 AC: 664 AN: 3814

European-Non Finnish (NFE) AF: 0.164 AC: 63337 AN: 385394

Other (OTH) AF: 0.213 AC: 7070 AN: 33212

GnomAD4 genome AF: 0.281 AC: 42802 AN: 152104 Hom.: 7855 Cov.: 32 AF XY: 0.282 AC XY: 20966 AN XY: 74356

African (AFR) AF: 0.515 AC: 21343 AN: 41474

American (AMR) AF: 0.224 AC: 3419 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 665 AN: 3466

East Asian (EAS) AF: 0.473 AC: 2444 AN: 5166

South Asian (SAS) AF: 0.233 AC: 1120 AN: 4816

European-Finnish (FIN) AF: 0.196 AC: 2075 AN: 10600

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10951 AN: 67980

Other (OTH) AF: 0.273 AC: 578 AN: 2114

Alfa AF: 0.194 Hom.: 4620

Bravo AF: 0.294

Asia WGS AF: 0.341 AC: 1185 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1

Mar 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.056
DANN	Benign	0.66
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6873124; hg19: chr5-169535734; COSMIC: COSV107383006;