11-17611128-C-T

Position:

• chr11-17611128-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001292063.2(OTOG):​c.5828C>T​(p.Thr1943Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,550,606 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (9 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.394

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032175183).
• BP6: Variant 11-17611128-C-T is Benign according to our data. Variant chr11-17611128-C-T is described in ClinVar as [Benign]. Clinvar id is 226901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17611128-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00616 (938/152364) while in subpopulation AFR AF= 0.0214 (890/41600). AF 95% confidence interval is 0.0202. There are 8 homozygotes in gnomad4. There are 433 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.5828C>T	p.Thr1943Met	missense_variant	36/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.5864C>T	p.Thr1955Met	missense_variant	35/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.5828C>T	p.Thr1943Met	missense_variant	36/56	5	NM_001292063.2	ENSP00000382329	P2
OTOG	ENST00000399391.7	c.5864C>T	p.Thr1955Met	missense_variant	35/55	5		ENSP00000382323	A2
OTOG	ENST00000342528.2	n.3166C>T		non_coding_transcript_exon_variant	12/22	2

Frequencies

GnomAD3 genomes AF: 0.00616 AC: 938 AN: 152246 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00139 AC: 205 AN: 147128 Hom.: 4 AF XY: 0.00111 AC XY: 88 AN XY: 79302

Gnomad AFR exome AF: 0.0262

Gnomad AMR exome AF: 0.000814

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000935

Gnomad OTH exome AF: 0.000701

GnomAD4 exome AF: 0.000667 AC: 932 AN: 1398242 Hom.: 9 Cov.: 36 AF XY: 0.000618 AC XY: 426 AN XY: 689650

Gnomad4 AFR exome AF: 0.0230

Gnomad4 AMR exome AF: 0.00104

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000839

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000621

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00616 AC: 938 AN: 152364 Hom.: 8 Cov.: 33 AF XY: 0.00581 AC XY: 433 AN XY: 74510

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00300 Hom.: 1

Bravo AF: 0.00668

ExAC AF: 0.00155 AC: 33

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Thr1955Met in exon 35 of OTOG: This variant is not expected to have clinical sig nificance because it has been identified in 3.4% (6/176) of Yoruba (Nigerian) ch romosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.n lm.nih.gov/projects/SNP; dbSNP rs75677194). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.33	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.071
Sift	Benign	0.098	T;.
Sift4G	Uncertain	0.0020	D;D
Vest4		0.064
MVP		0.14
ClinPred		0.014	T
GERP RS		-2.5
Varity_R		0.016
gMVP		0.38

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: rs75677194; hg19: chr11-17632675; COSMIC: COSV61132630;