rs144060182

Variant names:

• chr11-17578490-G-T
• rs144060182
• NM_001292063.2:c.2723G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17578490-G-T
• chr11-17578490-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001292063.2(OTOG):​c.2723G>T​(p.Arg908Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,539,486 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (24 hom.)
• Consequence: OTOG NM_001292063.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.92
• Publications: 1 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), 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077317357).
• BP6: Variant 11-17578490-G-T is Benign according to our data. Variant chr11-17578490-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00345 (526/152348) while in subpopulation NFE AF = 0.00557 (379/68028). AF 95% confidence interval is 0.00511. There are 1 homozygotes in GnomAd4. There are 230 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292063.2. 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.2723G>T	p.Arg908Leu	missense	Exon 23 of 56	NP_001278992.1	H9KVB3
	OTOG	NM_001277269.2		c.2759G>T	p.Arg920Leu	missense	Exon 22 of 55	NP_001264198.1	Q6ZRI0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOG	ENST00000399397.6	TSL:5 MANE Select	c.2723G>T	p.Arg908Leu	missense	Exon 23 of 56	ENSP00000382329.2	H9KVB3
	OTOG	ENST00000399391.7	TSL:5	c.2759G>T	p.Arg920Leu	missense	Exon 22 of 55	ENSP00000382323.2	Q6ZRI0-1
	OTOG	ENST00000342528.2	TSL:2	n.227G>T		non_coding_transcript_exon	Exon 1 of 22

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152230 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00557

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00339 AC: 472 AN: 139106 AF XY: 0.00336

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.000449

Gnomad ASJ exome AF: 0.00804

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00183

Gnomad NFE exome AF: 0.00646

Gnomad OTH exome AF: 0.00451

GnomAD4 exome AF: 0.00550 AC: 7631 AN: 1387138 Hom.: 24 Cov.: 32 AF XY: 0.00539 AC XY: 3691 AN XY: 684564

African (AFR) AF: 0.000728 AC: 23 AN: 31582

American (AMR) AF: 0.000701 AC: 25 AN: 35656

Ashkenazi Jewish (ASJ) AF: 0.00751 AC: 189 AN: 25164

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35718

South Asian (SAS) AF: 0.000240 AC: 19 AN: 79176

European-Finnish (FIN) AF: 0.00147 AC: 55 AN: 37506

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5686

European-Non Finnish (NFE) AF: 0.00649 AC: 7003 AN: 1078730

Other (OTH) AF: 0.00542 AC: 314 AN: 57920

GnomAD4 genome AF: 0.00345 AC: 526 AN: 152348 Hom.: 1 Cov.: 33 AF XY: 0.00309 AC XY: 230 AN XY: 74506

African (AFR) AF: 0.00135 AC: 56 AN: 41586

American (AMR) AF: 0.00202 AC: 31 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00557 AC: 379 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00217 Hom.: 1

Bravo AF: 0.00343

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00623 AC: 24

ExAC AF: 0.00226 AC: 48

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	OTOG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.9
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.079
Sift	Benign	0.29	T
Sift4G	Uncertain	0.013	D
Vest4		0.24
MVP		0.42
ClinPred		0.014	T
GERP RS		1.4
Varity_R		0.077
gMVP		0.39
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs144060182; hg19: chr11-17600037; COSMIC: COSV99063454;