chr12-80328678-T-C

Variant names:

• chr12-80328678-T-C
• rs114661503
• NM_001378609.3:c.4213T>C

Variant summary

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

The NM_001378609.3(OTOGL):​c.4213T>C​(p.Leu1405Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00229 in 1,602,674 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (21 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.55
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-80328678-T-C is Benign according to our data. Variant chr12-80328678-T-C is described in ClinVar as Benign. ClinVar VariationId is 226947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00903 (1376/152314) while in subpopulation AFR AF = 0.0275 (1143/41560). AF 95% confidence interval is 0.0262. There are 13 homozygotes in GnomAd4. There are 655 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.4213T>C	p.Leu1405Leu	synonymous	Exon 36 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.4213T>C	p.Leu1405Leu	synonymous	Exon 39 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.4213T>C	p.Leu1405Leu	synonymous	Exon 36 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.4213T>C	p.Leu1405Leu	synonymous	Exon 36 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.4078T>C	p.Leu1360Leu	synonymous	Exon 40 of 63	ENSP00000496036.1	A0A2R8YF04

Frequencies

GnomAD3 genomes AF: 0.00898 AC: 1367 AN: 152196 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.0150

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00393 AC: 968 AN: 246116 AF XY: 0.00326

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.0154

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000535

Gnomad OTH exome AF: 0.00316

GnomAD4 exome AF: 0.00158 AC: 2289 AN: 1450360 Hom.: 21 Cov.: 32 AF XY: 0.00147 AC XY: 1060 AN XY: 722286

African (AFR) AF: 0.0271 AC: 898 AN: 33158

American (AMR) AF: 0.00239 AC: 107 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 317 AN: 26042

East Asian (EAS) AF: 0.00916 AC: 363 AN: 39638

South Asian (SAS) AF: 0.000175 AC: 15 AN: 85902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00990 AC: 57 AN: 5758

European-Non Finnish (NFE) AF: 0.000240 AC: 264 AN: 1101788

Other (OTH) AF: 0.00447 AC: 268 AN: 60008

GnomAD4 genome AF: 0.00903 AC: 1376 AN: 152314 Hom.: 13 Cov.: 33 AF XY: 0.00879 AC XY: 655 AN XY: 74486

African (AFR) AF: 0.0275 AC: 1143 AN: 41560

American (AMR) AF: 0.00431 AC: 66 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3470

East Asian (EAS) AF: 0.0151 AC: 78 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68036

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00952 Hom.: 89

Bravo AF: 0.0106

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.0
DANN	Benign	0.80
PhyloP100		4.5
Mutation Taster		=96/4	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: rs114661503; hg19: chr12-80722458;