5-170108446-G-C

Position:

• chr5-170108446-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.58

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 (HGNC:):

ACMG classification

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	UniProt
FOXI1	NM_012188.5	c.972G>C	p.Pro324Pro	synonymous_variant	2/2	ENST00000306268.8	NP_036320.2
FOXI1	NM_144769.4	c.687G>C	p.Pro229Pro	synonymous_variant	2/2		NP_658982.1
FOXI1	XR_941092.2	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	c.972G>C	p.Pro324Pro	synonymous_variant	2/2	1	NM_012188.5	ENSP00000304286.5
FOXI1	ENST00000449804.4	c.687G>C	p.Pro229Pro	synonymous_variant	2/2	1		ENSP00000415483.2

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1829 AN: 152156 Hom.: 15 Cov.: 33

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.: 27 AF XY: 0.0122 AC XY: 1614 AN XY: 132330

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.: 34 AF XY: 0.0162 AC XY: 11683 AN XY: 719742

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.: 15 Cov.: 33 AF XY: 0.0116 AC XY: 864 AN XY: 74440

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.: 4

Bravo AF: 0.0104

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

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

Other links and lift over

dbSNP: rs56128152; hg19: chr5-169535450;