5-170108754-A-T

Variant names:

• chr5-170108754-A-T
• rs55762796
• NM_012188.5:c.*143A>T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXI1	NM_012188.5	c.*143A>T		3_prime_UTR_variant	Exon 2 of 2	ENST00000306268.8	NP_036320.2
FOXI1	NM_144769.4	c.*143A>T		3_prime_UTR_variant	Exon 2 of 2		NP_658982.1
FOXI1	XR_941092.2	n.1486A>T		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXI1	ENST00000306268.8	c.*143A>T		3_prime_UTR_variant	Exon 2 of 2	1	NM_012188.5	ENSP00000304286.5
FOXI1	ENST00000449804.4	c.*143A>T		3_prime_UTR_variant	Exon 2 of 2	1		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

Gnomad4 AFR exome AF: 0.0774

Gnomad4 AMR exome AF: 0.0292

Gnomad4 ASJ exome AF: 0.0401

Gnomad4 EAS exome AF: 0.0470

Gnomad4 SAS exome AF: 0.0846

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.0699

Gnomad4 OTH exome AF: 0.0621

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

Gnomad4 AFR AF: 0.0756

Gnomad4 AMR AF: 0.0519

Gnomad4 ASJ AF: 0.0447

Gnomad4 EAS AF: 0.0532

Gnomad4 SAS AF: 0.0864

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.0736

Gnomad4 OTH AF: 0.0601

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.4
DANN	Benign	0.87

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: rs55762796; hg19: chr5-169535758;