rs145653077

Variant names:

• chr12-80355852-G-A
• rs145653077
• NM_001378609.3:c.5710G>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.5710G>A​(p.Asp1904Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00349 in 1,613,898 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1904E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (51 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.29
• Publications: 8 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=0.009504139).
• BP6: Variant 12-80355852-G-A is Benign according to our data. Variant chr12-80355852-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00571 (869/152258) while in subpopulation NFE AF = 0.00487 (331/68020). AF 95% confidence interval is 0.00443. There are 13 homozygotes in GnomAd4. There are 556 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.5710G>A	p.Asp1904Asn	missense	Exon 47 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.5710G>A	p.Asp1904Asn	missense	Exon 50 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.5710G>A	p.Asp1904Asn	missense	Exon 47 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.5710G>A	p.Asp1904Asn	missense	Exon 47 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.5575G>A	p.Asp1859Asn	missense	Exon 51 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.1009G>A	p.Asp337Asn	missense	Exon 8 of 18	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.00571 AC: 869 AN: 152140 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00487

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00568 AC: 1401 AN: 246510 AF XY: 0.00535

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0388

Gnomad NFE exome AF: 0.00364

Gnomad OTH exome AF: 0.00548

GnomAD4 exome AF: 0.00325 AC: 4756 AN: 1461640 Hom.: 51 Cov.: 31 AF XY: 0.00324 AC XY: 2359 AN XY: 727096

African (AFR) AF: 0.000359 AC: 12 AN: 33472

American (AMR) AF: 0.00275 AC: 123 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00371 AC: 97 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0376 AC: 2006 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00209 AC: 2323 AN: 1111816

Other (OTH) AF: 0.00321 AC: 194 AN: 60374

GnomAD4 genome AF: 0.00571 AC: 869 AN: 152258 Hom.: 13 Cov.: 32 AF XY: 0.00747 AC XY: 556 AN XY: 74432

African (AFR) AF: 0.000289 AC: 12 AN: 41556

American (AMR) AF: 0.00288 AC: 44 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.0440 AC: 466 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00487 AC: 331 AN: 68020

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00355 Hom.: 8

Bravo AF: 0.00217

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.00241 AC: 20

ExAC AF: 0.00499 AC: 603

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	19
DANN	Benign	0.93
Eigen	Benign	0.12
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-1.1	T
PhyloP100		7.3
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.10
Sift	Benign	0.12	T
Sift4G	Benign	0.55	T
Vest4		0.30
MVP		0.22
MPC		0.041
ClinPred		0.035	T
GERP RS		4.3
gMVP		0.28
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: rs145653077; hg19: chr12-80749632;