NM_001378609.3:c.343A>C

Variant names:

• chr12-80222099-A-C
• rs200912084
• NM_001378609.3:c.343A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001378609.3(OTOGL):​c.343A>C​(p.Met115Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000672 in 1,597,538 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M115I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.84
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069841444).
• BP6: Variant 12-80222099-A-C is Benign according to our data. Variant chr12-80222099-A-C is described in ClinVar as Benign. ClinVar VariationId is 226938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00357 (544/152274) while in subpopulation AFR AF = 0.0125 (518/41558). AF 95% confidence interval is 0.0116. There are 6 homozygotes in GnomAd4. There are 260 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.343A>C	p.Met115Leu	missense	Exon 7 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.343A>C	p.Met115Leu	missense	Exon 10 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.343A>C	p.Met115Leu	missense	Exon 7 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.343A>C	p.Met115Leu	missense	Exon 7 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.343A>C	p.Met115Leu	missense	Exon 12 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000643417.1		n.1003A>C		non_coding_transcript_exon	Exon 10 of 23

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 543 AN: 152156 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000993 AC: 231 AN: 232562 AF XY: 0.000701

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000499

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000854

GnomAD4 exome AF: 0.000367 AC: 530 AN: 1445264 Hom.: 2 Cov.: 30 AF XY: 0.000313 AC XY: 225 AN XY: 719370

African (AFR) AF: 0.0138 AC: 459 AN: 33380

American (AMR) AF: 0.000427 AC: 19 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110728

Other (OTH) AF: 0.000731 AC: 44 AN: 60198

GnomAD4 genome AF: 0.00357 AC: 544 AN: 152274 Hom.: 6 Cov.: 32 AF XY: 0.00349 AC XY: 260 AN XY: 74458

African (AFR) AF: 0.0125 AC: 518 AN: 41558

American (AMR) AF: 0.000917 AC: 14 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00275 Hom.: 2

Bravo AF: 0.00407

ESP6500AA AF: 0.0106 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00110 AC: 131

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
DANN	Benign	0.92
Eigen	Benign	0.11
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.044
Sift	Benign	0.61	T
Sift4G	Benign	0.36	T
Vest4		0.23
MutPred		0.47		Loss of catalytic residue at G107 (P = 0.2074)
MVP		0.15
MPC		0.024
ClinPred		0.045	T
GERP RS		5.5
gMVP		0.12
Mutation Taster		=100/0	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: rs200912084; hg19: chr12-80615879;