NM_001292063.2:c.3423C>T

Variant names:

• chr11-17596052-C-T
• rs7122875
• NM_001292063.2:c.3423C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001292063.2(OTOG):​c.3423C>T​(p.Leu1141Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,550,724 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (37 hom.)
• Consequence: OTOG NM_001292063.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.347
• 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), 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 11-17596052-C-T is Benign according to our data. Variant chr11-17596052-C-T is described in ClinVar as Benign. ClinVar VariationId is 226887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.347 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.009 (1370/152248) while in subpopulation AFR AF = 0.0318 (1323/41546). AF 95% confidence interval is 0.0304. There are 16 homozygotes in GnomAd4. There are 639 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 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.3423C>T	p.Leu1141Leu	synonymous	Exon 29 of 56	NP_001278992.1
	OTOG	NM_001277269.2		c.3459C>T	p.Leu1153Leu	synonymous	Exon 28 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.3423C>T	p.Leu1141Leu	synonymous	Exon 29 of 56	ENSP00000382329.2
	OTOG	ENST00000399391.7	TSL:5	c.3459C>T	p.Leu1153Leu	synonymous	Exon 28 of 55	ENSP00000382323.2
	OTOG	ENST00000342528.2	TSL:2	n.788C>T		non_coding_transcript_exon	Exon 6 of 22

Frequencies

GnomAD3 genomes AF: 0.00899 AC: 1367 AN: 152130 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

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: 0.0000735

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00173 AC: 260 AN: 150428 AF XY: 0.00130

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.000936

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000537

Gnomad OTH exome AF: 0.000455

GnomAD4 exome AF: 0.000944 AC: 1320 AN: 1398476 Hom.: 37 Cov.: 31 AF XY: 0.000837 AC XY: 577 AN XY: 689752

African (AFR) AF: 0.0351 AC: 1108 AN: 31592

American (AMR) AF: 0.00112 AC: 40 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000631 AC: 5 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48306

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5698

European-Non Finnish (NFE) AF: 0.0000371 AC: 40 AN: 1078940

Other (OTH) AF: 0.00205 AC: 119 AN: 58092

GnomAD4 genome AF: 0.00900 AC: 1370 AN: 152248 Hom.: 16 Cov.: 33 AF XY: 0.00858 AC XY: 639 AN XY: 74434

African (AFR) AF: 0.0318 AC: 1323 AN: 41546

American (AMR) AF: 0.00216 AC: 33 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00143 Hom.: 1

Bravo AF: 0.0105

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.27
DANN	Benign	0.38
PhyloP100		-0.35
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7122875; hg19: chr11-17617599; COSMIC: COSV108886758;