rs1551122

Variant names:

• chr12-80372020-A-G
• rs1551122
• NM_001378609.3:c.6737A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-80372020-A-G
• chr12-80372020-A-T

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.6737A>G​(p.Asn2246Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.608 in 1,538,726 control chromosomes in the GnomAD database, including 294,099 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (22244 hom., cov: 32)
  • Exomes 𝑓: 0.62 (271855 hom.)
• Consequence: OTOGL NM_001378609.3 missense, splice_region
• Scores: Splicing: ADA: 0.8902
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.50
• Publications: 25 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=4.559077E-6).
• BP6: Variant 12-80372020-A-G is Benign according to our data. Variant chr12-80372020-A-G is described in ClinVar as Benign. ClinVar VariationId is 226972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.704 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.6737A>G	p.Asn2246Ser	missense splice_region	Exon 57 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.6737A>G	p.Asn2246Ser	missense splice_region	Exon 60 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.6737A>G	p.Asn2246Ser	missense splice_region	Exon 57 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.6737A>G	p.Asn2246Ser	missense splice_region	Exon 57 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.6602A>G	p.Asn2201Ser	missense splice_region	Exon 61 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.1931A>G	p.Asn644Ser	missense splice_region	Exon 16 of 18	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76353 AN: 151816 Hom.: 22245 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.635

Gnomad EAS AF: 0.724

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.545

GnomAD2 exomes AF: 0.581 AC: 122147 AN: 210322 AF XY: 0.597

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.383

Gnomad ASJ exome AF: 0.633

Gnomad EAS exome AF: 0.697

Gnomad FIN exome AF: 0.686

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.589

GnomAD4 exome AF: 0.619 AC: 859074 AN: 1386792 Hom.: 271855 Cov.: 28 AF XY: 0.622 AC XY: 429197 AN XY: 690076

African (AFR) AF: 0.170 AC: 5302 AN: 31220

American (AMR) AF: 0.405 AC: 15245 AN: 37622

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 15721 AN: 25014

East Asian (EAS) AF: 0.725 AC: 26217 AN: 36150

South Asian (SAS) AF: 0.633 AC: 48492 AN: 76638

European-Finnish (FIN) AF: 0.684 AC: 34007 AN: 49718

Middle Eastern (MID) AF: 0.529 AC: 2955 AN: 5586

European-Non Finnish (NFE) AF: 0.634 AC: 676510 AN: 1067436

Other (OTH) AF: 0.603 AC: 34625 AN: 57408

GnomAD4 genome AF: 0.503 AC: 76365 AN: 151934 Hom.: 22244 Cov.: 32 AF XY: 0.508 AC XY: 37717 AN XY: 74270

African (AFR) AF: 0.191 AC: 7919 AN: 41464

American (AMR) AF: 0.474 AC: 7234 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.635 AC: 2200 AN: 3462

East Asian (EAS) AF: 0.724 AC: 3742 AN: 5172

South Asian (SAS) AF: 0.626 AC: 3021 AN: 4828

European-Finnish (FIN) AF: 0.685 AC: 7224 AN: 10552

Middle Eastern (MID) AF: 0.541 AC: 157 AN: 290

European-Non Finnish (NFE) AF: 0.637 AC: 43269 AN: 67886

Other (OTH) AF: 0.546 AC: 1154 AN: 2112

Alfa AF: 0.602 Hom.: 89318

Bravo AF: 0.469

TwinsUK AF: 0.640 AC: 2372

ALSPAC AF: 0.641 AC: 2470

ESP6500AA AF: 0.215 AC: 948

ESP6500EA AF: 0.641 AC: 5509

ExAC AF: 0.584 AC: 70865

Asia WGS AF: 0.639 AC: 2207 AN: 3452

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0000046	T
MetaSVM	Benign	-0.99	T
PhyloP100		4.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.16
Sift	Benign	0.052	T
Sift4G	Uncertain	0.056	T
Vest4		0.17
MPC		0.17
ClinPred		0.021	T
GERP RS		6.0
gMVP		0.39
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.30
SpliceAI score (max)		0.16		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: rs1551122; hg19: chr12-80765800; COSMIC: COSV54014277; COSMIC: COSV54014277;