chr5-170108446-G-C

Position:

chr5-170108446-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_012188.5(FOXI1):c.972G>C(p.Pro324Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,602,972 control chromosomes in the GnomAD database, including 267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.012 ( 15 hom., cov: 33)

Exomes 𝑓: 0.017 ( 252 hom. )

Consequence

FOXI1
NM_012188.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -2.58

Variant links:

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 links:

FOXI1 (HGNC:):

FOXI1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 5-170108446-G-C is Benign according to our data. Variant chr5-170108446-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 352710.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}. Variant chr5-170108446-G-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.58 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1829/152274) while in subpopulation NFE AF= 0.019 (1291/68016). AF 95% confidence interval is 0.0181. There are 15 homozygotes in gnomad4. There are 864 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
FOXI1	NM_012188.5 linkuse as main transcript	c.972G>C	p.Pro324Pro	synonymous_variant	2/2	ENST00000306268.8	NP_036320.2
FOXI1	NM_144769.4 linkuse as main transcript	c.687G>C	p.Pro229Pro	synonymous_variant	2/2		NP_658982.1
FOXI1	XR_941092.2 linkuse as main transcript	n.1178G>C		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOXI1	ENST00000306268.8 linkuse as main transcript	c.972G>C	p.Pro324Pro	synonymous_variant	2/2	1	NM_012188.5	ENSP00000304286.5		Q12951-1
FOXI1	ENST00000449804.4 linkuse as main transcript	c.687G>C	p.Pro229Pro	synonymous_variant	2/2	1		ENSP00000415483.2		Q12951-2

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1829

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00700

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0190

Gnomad OTH

AF:

0.00958

GnomAD3 exomes

AF:

0.0122

AC:

3001

AN:

245174

Hom.:

AF XY:

0.0122

AC XY:

1614

AN XY:

132330

show subpopulations

Gnomad AFR exome

AF:

0.00296

Gnomad AMR exome

AF:

0.00472

Gnomad ASJ exome

AF:

0.00535

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00581

Gnomad FIN exome

AF:

0.0222

Gnomad NFE exome

AF:

0.0184

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.0167

AC:

24165

AN:

1450698

Hom.:

252

Cov.:

AF XY:

0.0162

AC XY:

11683

AN XY:

719742

show subpopulations

Gnomad4 AFR exome

AF:

0.00273

Gnomad4 AMR exome

AF:

0.00526

Gnomad4 ASJ exome

AF:

0.00560

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00595

Gnomad4 FIN exome

AF:

0.0227

Gnomad4 NFE exome

AF:

0.0192

Gnomad4 OTH exome

AF:

0.0135

GnomAD4 genome

AF:

0.0120

AC:

1829

AN:

152274

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

864

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00322

Gnomad4 AMR

AF:

0.00699

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00374

Gnomad4 FIN

AF:

0.0227

Gnomad4 NFE

AF:

0.0190

Gnomad4 OTH

AF:

0.00948

Alfa

AF:

0.0107

Hom.:

Bravo

AF:

0.0104

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2020	- -

Autosomal recessive nonsyndromic hearing loss 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.11

DANN

Benign

0.42

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over