rs145833172

Positions:

• chr11-17634154-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The ENST00000342528.2(OTOG):​n.4605+280A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,549,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: OTOG ENST00000342528.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.388

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00915575).
• BP6: Variant 11-17634154-A-C is Benign according to our data. Variant chr11-17634154-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 504787.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 = 0.00127 (193/152138) while in subpopulation AFR AF= 0.00438 (182/41514). AF 95% confidence interval is 0.00386. There are 0 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.7353A>C	p.Gln2451His	missense_variant	44/56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.7389A>C	p.Gln2463His	missense_variant	43/55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.7353A>C	p.Gln2451His	missense_variant	44/56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.7389A>C	p.Gln2463His	missense_variant	43/55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.4605+280A>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

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: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000177 AC: 26 AN: 146710 Hom.: 0 AF XY: 0.000114 AC XY: 9 AN XY: 79158

Gnomad AFR exome AF: 0.00355

Gnomad AMR exome AF: 0.0000814

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000923 AC: 129 AN: 1397718 Hom.: 0 Cov.: 32 AF XY: 0.0000740 AC XY: 51 AN XY: 689408

Gnomad4 AFR exome AF: 0.00345

Gnomad4 AMR exome AF: 0.000140

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: 0.000259

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74384

Gnomad4 AFR AF: 0.00438

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000608 Hom.: 0

Bravo AF: 0.00133

ExAC AF: 0.0000486 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 15, 2017

p.Gln2463His in exon 43 of OTOG: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (62/15180) of African chromos omeschromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org; dbSNP rs145833172). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.053
Sift	Benign	0.30	T;.
Sift4G	Uncertain	0.043	D;T
Vest4		0.23
MutPred		0.51		Loss of disorder (P = 0.1115);.;
MVP		0.061
ClinPred		0.022	T
GERP RS		-4.9
Varity_R		0.064
gMVP		0.54

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: rs145833172; hg19: chr11-17655701;