NM_001378609.3:c.124G>C

Variant names:

• chr12-80211953-G-C
• rs149117887
• NM_001378609.3:c.124G>C

Variant summary

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

The NM_001378609.3(OTOGL):​c.124G>C​(p.Gly42Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,417,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G42G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• Publications: 0 publications found

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

OTOGL Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 84B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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=0.07915142).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	NM_001378609.3	MANE Select	c.124G>C	p.Gly42Arg	missense	Exon 4 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.124G>C	p.Gly42Arg	missense	Exon 7 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.124G>C	p.Gly42Arg	missense	Exon 4 of 59	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.124G>C	p.Gly42Arg	missense	Exon 4 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.124G>C	p.Gly42Arg	missense	Exon 9 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000643417.1		n.784G>C		non_coding_transcript_exon	Exon 7 of 23

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1417324 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 702146

African (AFR) AF: 0.00 AC: 0 AN: 32974

American (AMR) AF: 0.00 AC: 0 AN: 40210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 38556

South Asian (SAS) AF: 0.00 AC: 0 AN: 81680

European-Finnish (FIN) AF: 0.0000267 AC: 1 AN: 37384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096092

Other (OTH) AF: 0.00 AC: 0 AN: 59194

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.93
Eigen	Benign	-0.095
Eigen_PC	Benign	0.033
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.6
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.018
Sift	Benign	0.73	T
Sift4G	Benign	0.20	T
Vest4		0.29
MutPred		0.17		Gain of MoRF binding (P = 0.05)
MVP		0.16
MPC		0.024
ClinPred		0.20	T
GERP RS		3.7
gMVP		0.27
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149117887; hg19: chr12-80605733;