rs542646349

chr11-17553197-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001292063.2(OTOG):c.371C>T(p.Pro124Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,550,468 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000084 (1 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.48

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03372124).
• BP6: Variant 11-17553197-C-T is Benign according to our data. Variant chr11-17553197-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517609.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOG	NM_001292063.2	c.371C>T	p.Pro124Leu	missense_variant	5/56	ENST00000399397.6
OTOG	NM_001277269.2	c.407C>T	p.Pro136Leu	missense_variant	4/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOG	ENST00000399397.6	c.371C>T	p.Pro124Leu	missense_variant	5/56	5	NM_001292063.2	P2
OTOG	ENST00000399391.7	c.407C>T	p.Pro136Leu	missense_variant	4/55	5		A2
OTOG	ENST00000428619.1	c.188C>T	p.Pro63Leu	missense_variant	3/4	3
OTOG	ENST00000498332.5	n.277C>T		non_coding_transcript_exon_variant	4/16	5

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000250 AC: 37 AN: 147926 Hom.: 0 AF XY: 0.000339 AC XY: 27 AN XY: 79736

Gnomad AFR exome AF: 0.000444

Gnomad AMR exome AF: 0.0000815

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00102

Gnomad SAS exome AF: 0.000843

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000844 AC: 118 AN: 1398186 Hom.: 1 Cov.: 31 AF XY: 0.000107 AC XY: 74 AN XY: 689626

Gnomad4 AFR exome AF: 0.000665

Gnomad4 AMR exome AF: 0.0000560

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000196

Gnomad4 SAS exome AF: 0.000669

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000250

Gnomad4 OTH exome AF: 0.000138

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74442

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.000166

ExAC AF: 0.000279 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2021

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 21, 2017

p.Pro136Leu in exon 4 of OTOG: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, three mammals (oranutang, cow, tenrec) have a leucine (Leu) at this position despite high nearby amino acid conservation. In addition, computational predict ion tools do not suggest a high likelihood of impact to the protein. It has also been identified in 0.1% (12/11744) of East Asian chromosomes and 38/173206 tota l chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadins titute.org; dbSNP rs542646349). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	20
Dann	Benign	0.62
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D;D;.
REVEL	Benign	0.083
Sift	Benign	0.12	T;D;.
Sift4G	Uncertain	0.010	D;D;D
Vest4		0.25
MVP		0.39
ClinPred		0.044	T
GERP RS		1.4
Varity_R		0.052
gMVP		0.32

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: rs542646349; hg19: chr11-17574744;