NM_012188.5:c.136C>T

Variant summary

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

The NM_012188.5(FOXI1):​c.136C>T​(p.Arg46Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R46R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FOXI1
NM_012188.5 missense

Scores

6
9
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.12
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, 0.777

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FOXI1NM_012188.5 linkc.136C>T p.Arg46Trp missense_variant Exon 1 of 2 ENST00000306268.8 NP_036320.2
FOXI1NM_144769.4 linkc.136C>T p.Arg46Trp missense_variant Exon 1 of 2 NP_658982.1
FOXI1XR_941092.2 linkn.197C>T non_coding_transcript_exon_variant Exon 1 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FOXI1ENST00000306268.8 linkc.136C>T p.Arg46Trp missense_variant Exon 1 of 2 1 NM_012188.5 ENSP00000304286.5 Q12951-1
FOXI1ENST00000449804.4 linkc.136C>T p.Arg46Trp missense_variant Exon 1 of 2 1 ENSP00000415483.2 Q12951-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461074
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726818
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
D;.
Eigen
Uncertain
0.27
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.82
T;T
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.78
D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Uncertain
2.5
M;M
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-4.1
D;D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.020
D;D
Polyphen
1.0
D;D
Vest4
0.59
MutPred
0.25
Loss of phosphorylation at S48 (P = 0.0517);Loss of phosphorylation at S48 (P = 0.0517);
MVP
0.95
MPC
0.73
ClinPred
1.0
D
GERP RS
3.6
Varity_R
0.38
gMVP
0.60

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: chr5-169533097; COSMIC: COSV60390308; API