rs6555887

Variant names:

• chr5-170109051-G-A
• rs6555887
• NM_012188.5:c.*440G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-170109051-G-A
• chr5-170109051-G-C
• chr5-170109051-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012188.5(FOXI1):​c.*440G>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 0.894 in 161,822 control chromosomes in the GnomAD database, including 64,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.89 (60903 hom., cov: 33)
  • Exomes 𝑓: 0.90 (3898 hom.)
• Consequence: FOXI1 NM_012188.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.268
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 5-170109051-G-A is Benign according to our data. Variant chr5-170109051-G-A is described in ClinVar as Benign. ClinVar VariationId is 352717.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 rank	MANE	Protein	UniProt
FOXI1	NM_012188.5	c.*440G>A		3_prime_UTR_variant	Exon 2 of 2	ENST00000306268.8	NP_036320.2
FOXI1	XR_941092.2	n.1783G>A		non_coding_transcript_exon_variant	Exon 3 of 3
FOXI1	NM_144769.4	c.*440G>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.*440G>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_012188.5	ENSP00000304286.5
FOXI1	ENST00000449804.4	c.*440G>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000415483.2

Frequencies

GnomAD3 genomes AF: 0.894 AC: 136004 AN: 152162 Hom.: 60860 Cov.: 33

Gnomad AFR AF: 0.860

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.908

Gnomad ASJ AF: 0.940

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.932

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.890

GnomAD4 exome AF: 0.903 AC: 8615 AN: 9542 Hom.: 3898 Cov.: 0 AF XY: 0.904 AC XY: 4478 AN XY: 4952

African (AFR) AF: 0.816 AC: 209 AN: 256

American (AMR) AF: 0.902 AC: 855 AN: 948

Ashkenazi Jewish (ASJ) AF: 0.939 AC: 261 AN: 278

East Asian (EAS) AF: 0.992 AC: 254 AN: 256

South Asian (SAS) AF: 0.933 AC: 603 AN: 646

European-Finnish (FIN) AF: 0.877 AC: 256 AN: 292

Middle Eastern (MID) AF: 0.813 AC: 26 AN: 32

European-Non Finnish (NFE) AF: 0.900 AC: 5673 AN: 6302

Other (OTH) AF: 0.898 AC: 478 AN: 532

GnomAD4 genome AF: 0.894 AC: 136102 AN: 152280 Hom.: 60903 Cov.: 33 AF XY: 0.892 AC XY: 66443 AN XY: 74458

African (AFR) AF: 0.860 AC: 35703 AN: 41536

American (AMR) AF: 0.908 AC: 13903 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.940 AC: 3263 AN: 3472

East Asian (EAS) AF: 0.986 AC: 5112 AN: 5182

South Asian (SAS) AF: 0.931 AC: 4498 AN: 4830

European-Finnish (FIN) AF: 0.864 AC: 9166 AN: 10608

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.905 AC: 61583 AN: 68030

Other (OTH) AF: 0.891 AC: 1881 AN: 2110

Alfa AF: 0.900 Hom.: 78009

Bravo AF: 0.895

Asia WGS AF: 0.942 AC: 3274 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.50
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: rs6555887; hg19: chr5-169536055;