NM_001378609.3:c.6421G>A

Variant names:

• chr12-80367650-G-A
• rs1551118
• NM_001378609.3:c.6421G>A

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.6421G>A​(p.Ala2141Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.808 in 1,525,446 control chromosomes in the GnomAD database, including 503,471 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (40662 hom., cov: 32)
  • Exomes 𝑓: 0.82 (462809 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.09
• Publications: 23 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=9.20896E-7).
• BP6: Variant 12-80367650-G-A is Benign according to our data. Variant chr12-80367650-G-A is described in ClinVar as Benign. ClinVar VariationId is 226969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.833 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.6421G>A	p.Ala2141Thr	missense	Exon 54 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.6421G>A	p.Ala2141Thr	missense	Exon 57 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.6421G>A	p.Ala2141Thr	missense	Exon 54 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.6421G>A	p.Ala2141Thr	missense	Exon 54 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.6286G>A	p.Ala2096Thr	missense	Exon 58 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.1615G>A	p.Ala539Thr	missense	Exon 13 of 18	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.714 AC: 108418 AN: 151916 Hom.: 40660 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.702

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.813

Gnomad FIN AF: 0.792

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.755

GnomAD2 exomes AF: 0.765 AC: 137747 AN: 180070 AF XY: 0.778

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.613

Gnomad ASJ exome AF: 0.832

Gnomad EAS exome AF: 0.760

Gnomad FIN exome AF: 0.791

Gnomad NFE exome AF: 0.833

Gnomad OTH exome AF: 0.777

GnomAD4 exome AF: 0.818 AC: 1123451 AN: 1373414 Hom.: 462809 Cov.: 33 AF XY: 0.820 AC XY: 558950 AN XY: 682006

African (AFR) AF: 0.436 AC: 12980 AN: 29790

American (AMR) AF: 0.633 AC: 21185 AN: 33490

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 19838 AN: 23812

East Asian (EAS) AF: 0.770 AC: 28849 AN: 37446

South Asian (SAS) AF: 0.819 AC: 62811 AN: 76702

European-Finnish (FIN) AF: 0.799 AC: 40958 AN: 51292

Middle Eastern (MID) AF: 0.758 AC: 4177 AN: 5508

European-Non Finnish (NFE) AF: 0.838 AC: 887064 AN: 1058406

Other (OTH) AF: 0.800 AC: 45589 AN: 56968

GnomAD4 genome AF: 0.713 AC: 108447 AN: 152032 Hom.: 40662 Cov.: 32 AF XY: 0.714 AC XY: 53070 AN XY: 74302

African (AFR) AF: 0.457 AC: 18938 AN: 41454

American (AMR) AF: 0.702 AC: 10707 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.840 AC: 2915 AN: 3470

East Asian (EAS) AF: 0.780 AC: 4027 AN: 5160

South Asian (SAS) AF: 0.812 AC: 3923 AN: 4830

European-Finnish (FIN) AF: 0.792 AC: 8370 AN: 10566

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.839 AC: 57039 AN: 67994

Other (OTH) AF: 0.755 AC: 1595 AN: 2112

Alfa AF: 0.798 Hom.: 157450

Bravo AF: 0.691

TwinsUK AF: 0.833 AC: 3088

ALSPAC AF: 0.844 AC: 3251

ESP6500AA AF: 0.483 AC: 2123

ESP6500EA AF: 0.839 AC: 7198

ExAC AF: 0.753 AC: 90385

Asia WGS AF: 0.781 AC: 2708 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.0
DANN	Benign	0.20
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	2.6	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.038
MPC		0.022
ClinPred		0.0014	T
GERP RS		3.0
PromoterAI		-0.012	Neutral
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs1551118; hg19: chr12-80761430; COSMIC: COSV54014259; COSMIC: COSV54014259;