5-170105976-C-A

Variant names:

• chr5-170105976-C-A
• rs1307118466
• NM_012188.5:c.19C>A

Variant summary

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

The NM_012188.5(FOXI1):​c.19C>A​(p.Pro7Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXI1 NM_012188.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59

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=0.19760758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXI1	NM_012188.5	c.19C>A	p.Pro7Thr	missense_variant	Exon 1 of 2	ENST00000306268.8	NP_036320.2
FOXI1	NM_144769.4	c.19C>A	p.Pro7Thr	missense_variant	Exon 1 of 2		NP_658982.1
FOXI1	XR_941092.2	n.80C>A		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXI1	ENST00000306268.8	c.19C>A	p.Pro7Thr	missense_variant	Exon 1 of 2	1	NM_012188.5	ENSP00000304286.5
FOXI1	ENST00000449804.4	c.19C>A	p.Pro7Thr	missense_variant	Exon 1 of 2	1		ENSP00000415483.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458426 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	0.0053	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	-0.065
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.2	L;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.20
Sift	Benign	0.063	T;D
Sift4G	Benign	0.072	T;D
Polyphen		0.32	B;B
Vest4		0.20
MutPred		0.14		Gain of phosphorylation at P7 (P = 0.0206);Gain of phosphorylation at P7 (P = 0.0206);
MVP		0.97
MPC		0.24
ClinPred		0.76	D
GERP RS		4.5
Varity_R		0.11
gMVP		0.17

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: rs1307118466; hg19: chr5-169532980;