5-170106034-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_012188.5(FOXI1):​c.77C>A​(p.Pro26His) variant causes a missense change. The variant allele was found at a frequency of 0.0000552 in 1,612,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

FOXI1
NM_012188.5 missense

Scores

3
12
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.91
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FOXI1NM_012188.5 linkuse as main transcriptc.77C>A p.Pro26His missense_variant 1/2 ENST00000306268.8 NP_036320.2
FOXI1NM_144769.4 linkuse as main transcriptc.77C>A p.Pro26His missense_variant 1/2 NP_658982.1
FOXI1XR_941092.2 linkuse as main transcriptn.138C>A non_coding_transcript_exon_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FOXI1ENST00000306268.8 linkuse as main transcriptc.77C>A p.Pro26His missense_variant 1/21 NM_012188.5 ENSP00000304286.5 Q12951-1
FOXI1ENST00000449804.4 linkuse as main transcriptc.77C>A p.Pro26His missense_variant 1/21 ENSP00000415483.2 Q12951-2

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152168
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000523
AC:
13
AN:
248636
Hom.:
0
AF XY:
0.0000594
AC XY:
8
AN XY:
134746
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000984
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000541
AC:
79
AN:
1460274
Hom.:
0
Cov.:
32
AF XY:
0.0000619
AC XY:
45
AN XY:
726462
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000375
Gnomad4 NFE exome
AF:
0.0000657
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152168
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000711
Hom.:
0
Bravo
AF:
0.0000491
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 29, 2023The c.77C>A (p.P26H) alteration is located in exon 1 (coding exon 1) of the FOXI1 gene. This alteration results from a C to A substitution at nucleotide position 77, causing the proline (P) at amino acid position 26 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 18, 2022This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 26 of the FOXI1 protein (p.Pro26His). This variant is present in population databases (rs373020583, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with FOXI1-related conditions. 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"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
0.0097
T
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.47
T;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.4
M;M
PrimateAI
Uncertain
0.61
T
PROVEAN
Uncertain
-2.4
N;N
REVEL
Uncertain
0.52
Sift
Uncertain
0.0060
D;D
Sift4G
Benign
0.067
T;D
Polyphen
1.0
D;D
Vest4
0.59
MVP
0.96
MPC
0.77
ClinPred
0.39
T
GERP RS
4.5
Varity_R
0.26
gMVP
0.48

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.

Other links and lift over

dbSNP: rs373020583; hg19: chr5-169533038; API