5-170106020-C-G

Variant names:

• chr5-170106020-C-G
• rs768858662
• NM_012188.5:c.63C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012188.5(FOXI1):​c.63C>G​(p.Ile21Met) 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. 13/22 in silico tools predict a benign 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. I21I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOXI1 NM_012188.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215
• Publications: 1 publications found

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]

FOXI1 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• autosomal recessive distal renal tubular acidosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Pendred syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss disorder

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• enlarged vestibular aqueduct syndrome

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15931535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOXI1	NM_012188.5	c.63C>G	p.Ile21Met	missense_variant	Exon 1 of 2	ENST00000306268.8	NP_036320.2
FOXI1	NM_144769.4	c.63C>G	p.Ile21Met	missense_variant	Exon 1 of 2		NP_658982.1
FOXI1	XR_941092.2	n.124C>G		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.63C>G	p.Ile21Met	missense_variant	Exon 1 of 2	1	NM_012188.5	ENSP00000304286.5
FOXI1	ENST00000449804.4	c.63C>G	p.Ile21Met	missense_variant	Exon 1 of 2	1		ENSP00000415483.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.0090	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	8.5
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		-0.21
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.0	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.28	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.66	P;P
Vest4		0.34
MutPred		0.13		Loss of glycosylation at S20 (P = 0.0523);Loss of glycosylation at S20 (P = 0.0523);
MVP		0.85
MPC		0.51
ClinPred		0.22	T
GERP RS		-1.3
PromoterAI		-0.021	Neutral
Varity_R		0.063
gMVP		0.11
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs768858662; hg19: chr5-169533024;