rs61729710

Variant names:

• chr12-80342124-T-A
• rs61729710
• NM_001378609.3:c.5227T>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_001378609.3(OTOGL):​c.5227T>A​(p.Leu1743Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000623 in 1,595,370 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.633
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009636909).
• BP6: Variant 12-80342124-T-A is Benign according to our data. Variant chr12-80342124-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226953.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 = 0.00329 (501/152300) while in subpopulation AFR AF = 0.0114 (473/41564). AF 95% confidence interval is 0.0105. There are 3 homozygotes in GnomAd4. There are 234 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.5227T>A	p.Leu1743Ile	missense	Exon 44 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.5227T>A	p.Leu1743Ile	missense	Exon 47 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.5227T>A	p.Leu1743Ile	missense	Exon 44 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.5227T>A	p.Leu1743Ile	missense	Exon 44 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.5092T>A	p.Leu1698Ile	missense	Exon 48 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.526T>A	p.Leu176Ile	missense	Exon 5 of 18	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 499 AN: 152182 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000833 AC: 180 AN: 216076 AF XY: 0.000714

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.000547

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000493

Gnomad NFE exome AF: 0.0000854

Gnomad OTH exome AF: 0.000551

GnomAD4 exome AF: 0.000342 AC: 493 AN: 1443070 Hom.: 1 Cov.: 32 AF XY: 0.000321 AC XY: 230 AN XY: 715812

African (AFR) AF: 0.00915 AC: 304 AN: 33238

American (AMR) AF: 0.000712 AC: 30 AN: 42116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25688

East Asian (EAS) AF: 0.00 AC: 0 AN: 39194

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83050

European-Finnish (FIN) AF: 0.000209 AC: 11 AN: 52518

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5746

European-Non Finnish (NFE) AF: 0.000103 AC: 113 AN: 1101800

Other (OTH) AF: 0.000553 AC: 33 AN: 59720

GnomAD4 genome AF: 0.00329 AC: 501 AN: 152300 Hom.: 3 Cov.: 32 AF XY: 0.00314 AC XY: 234 AN XY: 74468

African (AFR) AF: 0.0114 AC: 473 AN: 41564

American (AMR) AF: 0.00118 AC: 18 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000536 Hom.: 1

Bravo AF: 0.00361

ESP6500AA AF: 0.0101 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000987 AC: 119

Asia WGS AF: 0.000289 AC: 1 AN: 3472

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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.61	T
PhyloP100		0.63
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.39
Sift	Benign	0.26	T
Sift4G	Uncertain	0.022	D
Vest4		0.42
MVP		0.36
MPC		0.18
ClinPred		0.013	T
GERP RS		2.6
gMVP		0.47
Mutation Taster		=92/8	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: rs61729710; hg19: chr12-80735904;