Genetic Variant OTOG:p.Ser6Pro (chr11-17547388-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001292063.2(OTOG):c.16T>C(p.Ser6Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000793 in 1,261,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

OTOG
NM_001292063.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.00600

Variant links:

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]

OTOG links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0115226805).

BP6

Variant 11-17547388-T-C is Benign according to our data. Variant chr11-17547388-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 666740.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2 link	c.16T>C	p.Ser6Pro	missense_variant	Exon 1 of 56	ENST00000399397.6	NP_001278992.1	H9KVB3
OTOG	NM_001277269.2 link	c.16T>C	p.Ser6Pro	missense_variant	Exon 1 of 55		NP_001264198.1	Q6ZRI0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6 link	c.16T>C	p.Ser6Pro	missense_variant	Exon 1 of 56	5	NM_001292063.2	ENSP00000382329.2		H9KVB3
OTOG	ENST00000399391.7 link	c.16T>C	p.Ser6Pro	missense_variant	Exon 1 of 55	5		ENSP00000382323.2		Q6ZRI0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.93e-7

AC:

AN:

1261530

Hom.:

Cov.:

AF XY:

0.00000162

AC XY:

AN XY:

617830

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25582

American (AMR)

AF:

0.00

AC:

AN:

19584

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19454

East Asian (EAS)

AF:

0.00

AC:

AN:

29352

South Asian (SAS)

AF:

0.0000167

AC:

AN:

59828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4264

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1022140

Other (OTH)

AF:

0.00

AC:

AN:

51950

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000555

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 28, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ser6Pro variant in OTOG is classified as likely benign due to a lack of co nservation across species. Several species including mammals have Proline (Pro) at this position. ACMG/AMP Criteria applied: PM2, BP4_Strong. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.7

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.022

T;.

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0071

LIST_S2

Benign

0.34

T;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.42

N;.

PhyloP100

0.0060

PrimateAI

Benign

0.44

PROVEAN

Benign

0.94

N;.

REVEL

Benign

0.020

Sift

Benign

0.23

T;.

Sift4G

Benign

1.0

T;T

Vest4

0.14

MutPred

0.36

Loss of MoRF binding (P = 0.1206);Loss of MoRF binding (P = 0.1206);

MVP

0.092

ClinPred

0.055

GERP RS

-0.074

PromoterAI

0.26

Neutral

(source)

Varity_R

0.076

gMVP

0.088

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over