rs10063424

Variant names:

• chr5-170108518-T-C
• rs10063424
• NM_012188.5:c.1044T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012188.5(FOXI1):​c.1044T>C​(p.Tyr348Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,609,276 control chromosomes in the GnomAD database, including 667,570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (62367 hom., cov: 32)
  • Exomes 𝑓: 0.91 (605203 hom.)
• Consequence: FOXI1 NM_012188.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.667
• Publications: 29 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-170108518-T-C is Benign according to our data. Variant chr5-170108518-T-C is described in ClinVar as Benign. ClinVar VariationId is 260212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.667 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXI1	NM_012188.5	MANE Select	c.1044T>C	p.Tyr348Tyr	synonymous	Exon 2 of 2	NP_036320.2
	FOXI1	NM_144769.4		c.759T>C	p.Tyr253Tyr	synonymous	Exon 2 of 2	NP_658982.1	Q12951-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXI1	ENST00000306268.8	TSL:1 MANE Select	c.1044T>C	p.Tyr348Tyr	synonymous	Exon 2 of 2	ENSP00000304286.5	Q12951-1
	FOXI1	ENST00000449804.4	TSL:1	c.759T>C	p.Tyr253Tyr	synonymous	Exon 2 of 2	ENSP00000415483.2	Q12951-2

Frequencies

GnomAD3 genomes AF: 0.905 AC: 137631 AN: 152150 Hom.: 62314 Cov.: 32

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.912

Gnomad ASJ AF: 0.940

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.931

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.882

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.900

GnomAD2 exomes AF: 0.911 AC: 225284 AN: 247330 AF XY: 0.911

Gnomad AFR exome AF: 0.898

Gnomad AMR exome AF: 0.916

Gnomad ASJ exome AF: 0.934

Gnomad EAS exome AF: 0.987

Gnomad FIN exome AF: 0.862

Gnomad NFE exome AF: 0.901

Gnomad OTH exome AF: 0.900

GnomAD4 exome AF: 0.911 AC: 1327583 AN: 1457008 Hom.: 605203 Cov.: 51 AF XY: 0.912 AC XY: 660125 AN XY: 724206

African (AFR) AF: 0.898 AC: 30021 AN: 33422

American (AMR) AF: 0.914 AC: 40658 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.932 AC: 23996 AN: 25748

East Asian (EAS) AF: 0.987 AC: 39130 AN: 39628

South Asian (SAS) AF: 0.932 AC: 79713 AN: 85574

European-Finnish (FIN) AF: 0.862 AC: 45849 AN: 53172

Middle Eastern (MID) AF: 0.898 AC: 5154 AN: 5738

European-Non Finnish (NFE) AF: 0.909 AC: 1008470 AN: 1109098

Other (OTH) AF: 0.908 AC: 54592 AN: 60138

GnomAD4 genome AF: 0.905 AC: 137741 AN: 152268 Hom.: 62367 Cov.: 32 AF XY: 0.903 AC XY: 67236 AN XY: 74436

African (AFR) AF: 0.897 AC: 37276 AN: 41556

American (AMR) AF: 0.913 AC: 13954 AN: 15292

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

East Asian (EAS) AF: 0.986 AC: 5104 AN: 5174

South Asian (SAS) AF: 0.931 AC: 4496 AN: 4830

European-Finnish (FIN) AF: 0.864 AC: 9174 AN: 10614

Middle Eastern (MID) AF: 0.884 AC: 258 AN: 292

European-Non Finnish (NFE) AF: 0.905 AC: 61576 AN: 68012

Other (OTH) AF: 0.902 AC: 1906 AN: 2114

Alfa AF: 0.905 Hom.: 122779

Bravo AF: 0.907

Asia WGS AF: 0.944 AC: 3281 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 4 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.020
DANN	Benign	0.18
PhyloP100		-0.67
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: rs10063424; hg19: chr5-169535522; COSMIC: COSV108122747;