chr11-17599671-C-T

Variant names:

• chr11-17599671-C-T
• rs117005078
• NM_001292063.2:c.3683C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BS1_Supporting BS2

The NM_001277269.2(OTOG):​c.3719C>T​(p.Pro1240Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00483 in 1,550,638 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1240T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (17 hom.)
• Consequence: OTOG NM_001277269.2 missense, splice_region
• Scores: Splicing: ADA: 0.9945
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:5
• Conservation: PhyloP100: 7.05
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 18B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics
• 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: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0033 (502/152324) while in subpopulation NFE AF = 0.00591 (402/68024). AF 95% confidence interval is 0.00543. There are 0 homozygotes in GnomAd4. There are 227 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277269.2. 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
	OTOG	NM_001292063.2	MANE Select	c.3683C>T	p.Pro1228Leu	missense splice_region	Exon 31 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.3719C>T	p.Pro1240Leu	missense splice_region	Exon 30 of 55	NP_001264198.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.3683C>T	p.Pro1228Leu	missense splice_region	Exon 31 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.3719C>T	p.Pro1240Leu	missense splice_region	Exon 30 of 55	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.1048-2539C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00591

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00273 AC: 409 AN: 149550 AF XY: 0.00241

Gnomad AFR exome AF: 0.000881

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00196

Gnomad NFE exome AF: 0.00555

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00500 AC: 6985 AN: 1398314 Hom.: 17 Cov.: 31 AF XY: 0.00487 AC XY: 3361 AN XY: 689684

African (AFR) AF: 0.000633 AC: 20 AN: 31596

American (AMR) AF: 0.00157 AC: 56 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.000199 AC: 5 AN: 25180

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35736

South Asian (SAS) AF: 0.000896 AC: 71 AN: 79234

European-Finnish (FIN) AF: 0.00290 AC: 140 AN: 48226

Middle Eastern (MID) AF: 0.000702 AC: 4 AN: 5698

European-Non Finnish (NFE) AF: 0.00599 AC: 6468 AN: 1078922

Other (OTH) AF: 0.00379 AC: 220 AN: 58016

GnomAD4 genome AF: 0.00330 AC: 502 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.00305 AC XY: 227 AN XY: 74488

African (AFR) AF: 0.00103 AC: 43 AN: 41576

American (AMR) AF: 0.00183 AC: 28 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00591 AC: 402 AN: 68024

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00502 Hom.: 6

Bravo AF: 0.00323

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00727 AC: 28

ExAC AF: 0.00132 AC: 30

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
1	1	-	Meniere disease (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.076	T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Vest4		0.90
MVP		0.80
ClinPred		0.11	T
GERP RS		5.3
Varity_R		0.29
gMVP		0.84
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.93
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: rs117005078; hg19: chr11-17621218;