5-170106029-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012188.5(FOXI1):c.72G>T(p.Glu24Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXI1 NM_012188.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22821528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXI1	NM_012188.5	c.72G>T	p.Glu24Asp	missense_variant	1/2	ENST00000306268.8
FOXI1	NM_144769.4	c.72G>T	p.Glu24Asp	missense_variant	1/2
FOXI1	XR_941092.2	n.133G>T		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXI1	ENST00000306268.8	c.72G>T	p.Glu24Asp	missense_variant	1/2	1	NM_012188.5	P1
FOXI1	ENST00000449804.4	c.72G>T	p.Glu24Asp	missense_variant	1/2	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 05, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with FOXI1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 24 of the FOXI1 protein (p.Glu24Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	0.068
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.58
Sift	Benign	0.030	D;T
Sift4G	Benign	0.090	T;T
Polyphen		0.60	P;P
Vest4		0.28
MutPred		0.083		Gain of relative solvent accessibility (P = 0.1894);Gain of relative solvent accessibility (P = 0.1894);
MVP		0.93
MPC		0.67
ClinPred		0.92	D
GERP RS		3.6
Varity_R		0.27
gMVP		0.18

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-169533033;