rs61735664

Variant names:

• chr12-80341957-A-G
• rs61735664
• NM_001378609.3:c.5060A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378609.3(OTOGL):​c.5060A>G​(p.Asn1687Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0483 in 1,600,182 control chromosomes in the GnomAD database, including 2,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (158 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2062 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.16
• 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 (MetaRNN=0.0050604045).
• BP6: Variant 12-80341957-A-G is Benign according to our data. Variant chr12-80341957-A-G is described in ClinVar as Benign. ClinVar VariationId is 226950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

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.5060A>G	p.Asn1687Ser	missense	Exon 44 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.5060A>G	p.Asn1687Ser	missense	Exon 47 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.5060A>G	p.Asn1687Ser	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.5060A>G	p.Asn1687Ser	missense	Exon 44 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.4925A>G	p.Asn1642Ser	missense	Exon 48 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.359A>G	p.Asn120Ser	missense	Exon 5 of 18	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5482 AN: 152164 Hom.: 159 Cov.: 32

Gnomad AFR AF: 0.00997

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0549

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0541

Gnomad OTH AF: 0.0488

GnomAD2 exomes AF: 0.0370 AC: 8624 AN: 233194 AF XY: 0.0373

Gnomad AFR exome AF: 0.00880

Gnomad AMR exome AF: 0.0378

Gnomad ASJ exome AF: 0.0488

Gnomad EAS exome AF: 0.000116

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.0545

Gnomad OTH exome AF: 0.0498

GnomAD4 exome AF: 0.0496 AC: 71810 AN: 1447900 Hom.: 2062 Cov.: 29 AF XY: 0.0489 AC XY: 35170 AN XY: 719514

African (AFR) AF: 0.00895 AC: 298 AN: 33304

American (AMR) AF: 0.0389 AC: 1700 AN: 43674

Ashkenazi Jewish (ASJ) AF: 0.0477 AC: 1232 AN: 25804

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39456

South Asian (SAS) AF: 0.0180 AC: 1510 AN: 84058

European-Finnish (FIN) AF: 0.0156 AC: 827 AN: 53052

Middle Eastern (MID) AF: 0.0685 AC: 382 AN: 5574

European-Non Finnish (NFE) AF: 0.0571 AC: 63029 AN: 1103038

Other (OTH) AF: 0.0471 AC: 2826 AN: 59940

GnomAD4 genome AF: 0.0360 AC: 5479 AN: 152282 Hom.: 158 Cov.: 32 AF XY: 0.0348 AC XY: 2592 AN XY: 74456

African (AFR) AF: 0.00994 AC: 413 AN: 41562

American (AMR) AF: 0.0548 AC: 838 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5194

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4822

European-Finnish (FIN) AF: 0.0129 AC: 137 AN: 10614

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.0541 AC: 3679 AN: 68012

Other (OTH) AF: 0.0483 AC: 102 AN: 2112

Alfa AF: 0.0491 Hom.: 676

Bravo AF: 0.0384

TwinsUK AF: 0.0580 AC: 215

ALSPAC AF: 0.0563 AC: 217

ESP6500AA AF: 0.0114 AC: 41

ESP6500EA AF: 0.0552 AC: 451

ExAC AF: 0.0362 AC: 4366

Asia WGS AF: 0.00983 AC: 34 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.58	T
PhyloP100		7.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.24
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.015	D
Vest4		0.51
MPC		0.17
ClinPred		0.0041	T
GERP RS		5.0
gMVP		0.55
Mutation Taster		=85/15	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs61735664; hg19: chr12-80735737; COSMIC: COSV54020765; COSMIC: COSV54020765;