rs146572555

Variant names:

• chr12-80370580-C-T
• rs146572555
• NM_001378609.3:c.6626C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-80370580-C-T
• chr12-80370580-C-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.6626C>T​(p.Thr2209Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000771 in 1,534,932 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (7 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.87
• Publications: 5 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=0.012212127).
• BP6: Variant 12-80370580-C-T is Benign according to our data. Variant chr12-80370580-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226971.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 = 0.00178 (270/151882) while in subpopulation AFR AF = 0.00398 (165/41462). AF 95% confidence interval is 0.00348. There are 1 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.6626C>T	p.Thr2209Ile	missense	Exon 56 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.6626C>T	p.Thr2209Ile	missense	Exon 59 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.6626C>T	p.Thr2209Ile	missense	Exon 56 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.6626C>T	p.Thr2209Ile	missense	Exon 56 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.6491C>T	p.Thr2164Ile	missense	Exon 60 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.1820C>T	p.Thr607Ile	missense	Exon 15 of 18	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 151764 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00394

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00283

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000737

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.000987 AC: 199 AN: 201562 AF XY: 0.000962

Gnomad AFR exome AF: 0.00485

Gnomad AMR exome AF: 0.00195

Gnomad ASJ exome AF: 0.000762

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000743

Gnomad OTH exome AF: 0.00240

GnomAD4 exome AF: 0.000660 AC: 913 AN: 1383050 Hom.: 7 Cov.: 29 AF XY: 0.000651 AC XY: 447 AN XY: 686818

African (AFR) AF: 0.00468 AC: 139 AN: 29676

American (AMR) AF: 0.00252 AC: 83 AN: 33000

Ashkenazi Jewish (ASJ) AF: 0.000555 AC: 13 AN: 23410

East Asian (EAS) AF: 0.00 AC: 0 AN: 36742

South Asian (SAS) AF: 0.0000978 AC: 7 AN: 71550

European-Finnish (FIN) AF: 0.0000391 AC: 2 AN: 51170

Middle Eastern (MID) AF: 0.00804 AC: 44 AN: 5470

European-Non Finnish (NFE) AF: 0.000478 AC: 514 AN: 1075122

Other (OTH) AF: 0.00195 AC: 111 AN: 56910

GnomAD4 genome AF: 0.00178 AC: 270 AN: 151882 Hom.: 1 Cov.: 32 AF XY: 0.00162 AC XY: 120 AN XY: 74236

African (AFR) AF: 0.00398 AC: 165 AN: 41462

American (AMR) AF: 0.00276 AC: 42 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000737 AC: 50 AN: 67880

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00109 Hom.: 1

Bravo AF: 0.00213

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000997 AC: 121

Asia WGS AF: 0.00145 AC: 5 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.96
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.9
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.077
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.081	T
Vest4		0.29
MVP		0.085
MPC		0.024
ClinPred		0.023	T
GERP RS		0.12
gMVP		0.39
Mutation Taster		=85/15	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: rs146572555; hg19: chr12-80764360;