rs77823283

Variant names:

• chr5-170109167-A-G
• rs77823283
• NM_012188.5:c.*556A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_012188.5(FOXI1):​c.*556A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 154,204 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (0 hom.)
• Consequence: FOXI1 NM_012188.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.66
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-170109167-A-G is Benign according to our data. Variant chr5-170109167-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 905481.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 15 Unknown,AR gene

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.*556A>G		3_prime_UTR	Exon 2 of 2	NP_036320.2
	FOXI1	NM_144769.4		c.*556A>G		3_prime_UTR	Exon 2 of 2	NP_658982.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXI1	ENST00000306268.8	TSL:1 MANE Select	c.*556A>G		3_prime_UTR	Exon 2 of 2	ENSP00000304286.5
	FOXI1	ENST00000449804.4	TSL:1	c.*556A>G		3_prime_UTR	Exon 2 of 2	ENSP00000415483.2

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1648 AN: 152152 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.0375

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.00812

GnomAD4 exome AF: 0.00672 AC: 13 AN: 1934 Hom.: 0 Cov.: 0 AF XY: 0.00818 AC XY: 8 AN XY: 978

African (AFR) AF: 0.00 AC: 0 AN: 14

American (AMR) AF: 0.00256 AC: 1 AN: 390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14

East Asian (EAS) AF: 0.00 AC: 0 AN: 22

South Asian (SAS) AF: 0.0122 AC: 1 AN: 82

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00845 AC: 11 AN: 1302

Other (OTH) AF: 0.00 AC: 0 AN: 80

GnomAD4 genome AF: 0.0108 AC: 1647 AN: 152270 Hom.: 15 Cov.: 32 AF XY: 0.0115 AC XY: 856 AN XY: 74448

African (AFR) AF: 0.00253 AC: 105 AN: 41552

American (AMR) AF: 0.00575 AC: 88 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4818

European-Finnish (FIN) AF: 0.0375 AC: 398 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0146 AC: 996 AN: 68022

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00848 Hom.: 2

Bravo AF: 0.00822

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive nonsyndromic hearing loss 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.22
DANN	Benign	0.78
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism

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: rs77823283; hg19: chr5-169536171;