chr5-170108754-A-T

Variant names:

• chr5-170108754-A-T
• rs55762796
• NM_012188.5:c.*143A>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.*143A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0704 in 694,544 control chromosomes in the GnomAD database, including 1,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (472 hom., cov: 33)
  • Exomes 𝑓: 0.069 (1488 hom.)
• Consequence: FOXI1 NM_012188.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.267
• Publications: 4 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=-0.78).
• BP6: Variant 5-170108754-A-T is Benign according to our data. Variant chr5-170108754-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 904689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0796 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012188.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXI1	NM_012188.5	MANE Select	c.*143A>T		3_prime_UTR	Exon 2 of 2	NP_036320.2
	FOXI1	NM_144769.4		c.*143A>T		3_prime_UTR	Exon 2 of 2	NP_658982.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXI1	ENST00000306268.8	TSL:1 MANE Select	c.*143A>T		3_prime_UTR	Exon 2 of 2	ENSP00000304286.5
	FOXI1	ENST00000449804.4	TSL:1	c.*143A>T		3_prime_UTR	Exon 2 of 2	ENSP00000415483.2

Frequencies

GnomAD3 genomes AF: 0.0743 AC: 11306 AN: 152132 Hom.: 473 Cov.: 33

Gnomad AFR AF: 0.0757

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.0520

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.0530

Gnomad SAS AF: 0.0862

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0736

Gnomad OTH AF: 0.0607

GnomAD4 exome AF: 0.0693 AC: 37574 AN: 542294 Hom.: 1488 Cov.: 6 AF XY: 0.0704 AC XY: 20562 AN XY: 292004

African (AFR) AF: 0.0774 AC: 1176 AN: 15186

American (AMR) AF: 0.0292 AC: 874 AN: 29976

Ashkenazi Jewish (ASJ) AF: 0.0401 AC: 675 AN: 16814

East Asian (EAS) AF: 0.0470 AC: 1526 AN: 32482

South Asian (SAS) AF: 0.0846 AC: 4694 AN: 55500

European-Finnish (FIN) AF: 0.110 AC: 4025 AN: 36550

Middle Eastern (MID) AF: 0.0538 AC: 157 AN: 2916

European-Non Finnish (NFE) AF: 0.0699 AC: 22602 AN: 323140

Other (OTH) AF: 0.0621 AC: 1845 AN: 29730

GnomAD4 genome AF: 0.0743 AC: 11308 AN: 152250 Hom.: 472 Cov.: 33 AF XY: 0.0748 AC XY: 5567 AN XY: 74422

African (AFR) AF: 0.0756 AC: 3142 AN: 41554

American (AMR) AF: 0.0519 AC: 794 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3470

East Asian (EAS) AF: 0.0532 AC: 275 AN: 5172

South Asian (SAS) AF: 0.0864 AC: 417 AN: 4824

European-Finnish (FIN) AF: 0.115 AC: 1215 AN: 10602

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0736 AC: 5003 AN: 68012

Other (OTH) AF: 0.0601 AC: 127 AN: 2114

Alfa AF: 0.0324 Hom.: 25

Bravo AF: 0.0678

Asia WGS AF: 0.0570 AC: 201 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Autosomal recessive nonsyndromic hearing loss 4 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.4
DANN	Benign	0.87
PhyloP100		-0.27
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: rs55762796; hg19: chr5-169535758;