rs2112669

Variant names:

• chr5-170106785-C-G
• rs2112669
• NM_012188.5:c.574+254C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-170106785-C-G
• chr5-170106785-C-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.574+254C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 258,914 control chromosomes in the GnomAD database, including 9,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (8075 hom., cov: 34)
  • Exomes 𝑓: 0.18 (1857 hom.)
• Consequence: FOXI1 NM_012188.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.166
• Publications: 2 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=-0.85).
• BP6: Variant 5-170106785-C-G is Benign according to our data. Variant chr5-170106785-C-G is described in ClinVar as Benign. ClinVar VariationId is 1237049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXI1	NM_012188.5	c.574+254C>G		intron_variant	Intron 1 of 1	ENST00000306268.8	NP_036320.2
FOXI1	NM_144769.4	c.574+254C>G		intron_variant	Intron 1 of 1		NP_658982.1
FOXI1	XR_941092.2	n.636-132C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXI1	ENST00000306268.8	c.574+254C>G		intron_variant	Intron 1 of 1	1	NM_012188.5	ENSP00000304286.5
FOXI1	ENST00000449804.4	c.574+254C>G		intron_variant	Intron 1 of 1	1		ENSP00000415483.2

Frequencies

GnomAD3 genomes AF: 0.284 AC: 43177 AN: 152116 Hom.: 8050 Cov.: 34

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.268

GnomAD4 exome AF: 0.177 AC: 18892 AN: 106680 Hom.: 1857 AF XY: 0.177 AC XY: 9020 AN XY: 51028

African (AFR) AF: 0.583 AC: 1179 AN: 2024

American (AMR) AF: 0.186 AC: 22 AN: 118

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 118 AN: 674

East Asian (EAS) AF: 0.457 AC: 202 AN: 442

South Asian (SAS) AF: 0.218 AC: 451 AN: 2070

European-Finnish (FIN) AF: 0.267 AC: 8 AN: 30

Middle Eastern (MID) AF: 0.186 AC: 35 AN: 188

European-Non Finnish (NFE) AF: 0.165 AC: 16135 AN: 97614

Other (OTH) AF: 0.211 AC: 742 AN: 3520

GnomAD4 genome AF: 0.284 AC: 43251 AN: 152234 Hom.: 8075 Cov.: 34 AF XY: 0.284 AC XY: 21157 AN XY: 74420

African (AFR) AF: 0.523 AC: 21737 AN: 41526

American (AMR) AF: 0.225 AC: 3437 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 668 AN: 3472

East Asian (EAS) AF: 0.472 AC: 2444 AN: 5180

South Asian (SAS) AF: 0.234 AC: 1129 AN: 4830

European-Finnish (FIN) AF: 0.196 AC: 2072 AN: 10584

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10974 AN: 68018

Other (OTH) AF: 0.275 AC: 580 AN: 2112

Alfa AF: 0.117 Hom.: 222

Bravo AF: 0.297

Asia WGS AF: 0.339 AC: 1180 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 11, 2018

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	-0.85
CADD	Benign	6.4
DANN	Benign	0.34
PhyloP100		0.17
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: rs2112669; hg19: chr5-169533789;