5-170106000-A-C

Variant summary

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

The NM_012188.5(FOXI1):c.43A>C(p.Ser15Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 5.04

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXI1	NM_012188.5	c.43A>C	p.Ser15Arg	missense_variant	1/2	ENST00000306268.8
FOXI1	NM_144769.4	c.43A>C	p.Ser15Arg	missense_variant	1/2
FOXI1	XR_941092.2	n.104A>C		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXI1	ENST00000306268.8	c.43A>C	p.Ser15Arg	missense_variant	1/2	1	NM_012188.5	P1
FOXI1	ENST00000449804.4	c.43A>C	p.Ser15Arg	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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.43A>C (p.S15R) alteration is located in exon 1 (coding exon 1) of the FOXI1 gene. This alteration results from a A to C substitution at nucleotide position 43, causing the serine (S) at amino acid position 15 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.021	D;D
Sift4G	Benign	0.078	T;T
Polyphen		0.95	P;D
Vest4		0.55
MutPred		0.15		Loss of phosphorylation at S15 (P = 0.0099);Loss of phosphorylation at S15 (P = 0.0099);
MVP		0.95
MPC		0.66
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.16
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-169533004;