rs73139245

Variant names:

• chr12-80356818-T-C
• rs73139245
• NM_001378609.3:c.5923T>C

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_001378609.3(OTOGL):​c.5923T>C​(p.Leu1975Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0054 in 1,593,886 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (28 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0700
• Publications: 1 publications found

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

OTOGL Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 84B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• 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=-0.8).
• BP6: Variant 12-80356818-T-C is Benign according to our data. Variant chr12-80356818-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00522 (794/152224) while in subpopulation NFE AF = 0.00766 (521/68010). AF 95% confidence interval is 0.00712. There are 5 homozygotes in GnomAd4. There are 428 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. 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
	OTOGL	NM_001378609.3	MANE Select	c.5923T>C	p.Leu1975Leu	synonymous	Exon 49 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.5923T>C	p.Leu1975Leu	synonymous	Exon 52 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.5923T>C	p.Leu1975Leu	synonymous	Exon 49 of 59	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.5923T>C	p.Leu1975Leu	synonymous	Exon 49 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.5788T>C	p.Leu1930Leu	synonymous	Exon 53 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.1222T>C	p.Leu408Leu	synonymous	Exon 10 of 18	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 795 AN: 152106 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00767

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00566 AC: 1318 AN: 232748 AF XY: 0.00576

Gnomad AFR exome AF: 0.000837

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00126

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0169

Gnomad NFE exome AF: 0.00824

Gnomad OTH exome AF: 0.00537

GnomAD4 exome AF: 0.00542 AC: 7814 AN: 1441662 Hom.: 28 Cov.: 29 AF XY: 0.00544 AC XY: 3896 AN XY: 716728

African (AFR) AF: 0.000768 AC: 25 AN: 32552

American (AMR) AF: 0.00113 AC: 47 AN: 41574

Ashkenazi Jewish (ASJ) AF: 0.00106 AC: 27 AN: 25542

East Asian (EAS) AF: 0.00 AC: 0 AN: 38820

South Asian (SAS) AF: 0.0000366 AC: 3 AN: 82008

European-Finnish (FIN) AF: 0.0144 AC: 766 AN: 53012

Middle Eastern (MID) AF: 0.000705 AC: 4 AN: 5674

European-Non Finnish (NFE) AF: 0.00608 AC: 6701 AN: 1103016

Other (OTH) AF: 0.00405 AC: 241 AN: 59464

GnomAD4 genome AF: 0.00522 AC: 794 AN: 152224 Hom.: 5 Cov.: 32 AF XY: 0.00575 AC XY: 428 AN XY: 74420

African (AFR) AF: 0.000650 AC: 27 AN: 41552

American (AMR) AF: 0.00170 AC: 26 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0199 AC: 211 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00766 AC: 521 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00556 Hom.: 2

Bravo AF: 0.00345

Asia WGS AF: 0.00115 AC: 4 AN: 3476

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.1
DANN	Benign	0.68
PhyloP100		0.070
Mutation Taster		=100/0	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: rs73139245; hg19: chr12-80750598; COSMIC: COSV54024860; COSMIC: COSV54024860;