chr5-170106602-T-C

Variant names:

• chr5-170106602-T-C
• rs2277945
• NM_012188.5:c.574+71T>C

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+71T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 1,587,342 control chromosomes in the GnomAD database, including 85,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.27 (6281 hom., cov: 33)
  • Exomes 𝑓: 0.33 (79555 hom.)
• Consequence: FOXI1 NM_012188.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0800
• Publications: 8 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=-0.76).
• BP6: Variant 5-170106602-T-C is Benign according to our data. Variant chr5-170106602-T-C is described in ClinVar as Benign. ClinVar VariationId is 1297806.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXI1	NM_012188.5	c.574+71T>C		intron_variant	Intron 1 of 1	ENST00000306268.8	NP_036320.2
FOXI1	NM_144769.4	c.574+71T>C		intron_variant	Intron 1 of 1		NP_658982.1
FOXI1	XR_941092.2	n.635+71T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXI1	ENST00000306268.8	c.574+71T>C		intron_variant	Intron 1 of 1	1	NM_012188.5	ENSP00000304286.5
FOXI1	ENST00000449804.4	c.574+71T>C		intron_variant	Intron 1 of 1	1		ENSP00000415483.2

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41503 AN: 152064 Hom.: 6287 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.260

GnomAD4 exome AF: 0.331 AC: 474375 AN: 1435160 Hom.: 79555 AF XY: 0.331 AC XY: 235681 AN XY: 712230

African (AFR) AF: 0.134 AC: 4385 AN: 32706

American (AMR) AF: 0.295 AC: 11898 AN: 40270

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 8876 AN: 25588

East Asian (EAS) AF: 0.302 AC: 11562 AN: 38324

South Asian (SAS) AF: 0.335 AC: 28053 AN: 83634

European-Finnish (FIN) AF: 0.244 AC: 12557 AN: 51466

Middle Eastern (MID) AF: 0.277 AC: 1591 AN: 5738

European-Non Finnish (NFE) AF: 0.343 AC: 376407 AN: 1097944

Other (OTH) AF: 0.320 AC: 19046 AN: 59490

GnomAD4 genome AF: 0.273 AC: 41487 AN: 152182 Hom.: 6281 Cov.: 33 AF XY: 0.272 AC XY: 20242 AN XY: 74402

African (AFR) AF: 0.140 AC: 5808 AN: 41532

American (AMR) AF: 0.314 AC: 4809 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1200 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1522 AN: 5164

South Asian (SAS) AF: 0.317 AC: 1527 AN: 4818

European-Finnish (FIN) AF: 0.239 AC: 2532 AN: 10612

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23183 AN: 67964

Other (OTH) AF: 0.257 AC: 543 AN: 2114

Alfa AF: 0.332 Hom.: 6926

Bravo AF: 0.272

Asia WGS AF: 0.283 AC: 980 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	-0.76
CADD	Benign	8.6
DANN	Benign	0.85
PhyloP100		-0.080
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: rs2277945; hg19: chr5-169533606; COSMIC: COSV60388292;