NM_001378609.3:c.6247A>G

Variant names:

• chr12-80358880-A-G
• rs2034528
• NM_001378609.3:c.6247A>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.6247A>G​(p.Ile2083Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.929 in 1,505,062 control chromosomes in the GnomAD database, including 649,613 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2083T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.94 (67607 hom., cov: 32)
  • Exomes 𝑓: 0.93 (582006 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.553
• 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: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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=6.47368E-7).
• BP6: Variant 12-80358880-A-G is Benign according to our data. Variant chr12-80358880-A-G is described in ClinVar as Benign. ClinVar VariationId is 226966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 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.6247A>G	p.Ile2083Val	missense	Exon 52 of 59	NP_001365538.2
	OTOGL	NM_001378610.3		c.6247A>G	p.Ile2083Val	missense	Exon 55 of 62	NP_001365539.2
	OTOGL	NM_173591.7		c.6247A>G	p.Ile2083Val	missense	Exon 52 of 59	NP_775862.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.6247A>G	p.Ile2083Val	missense	Exon 52 of 59	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.6112A>G	p.Ile2038Val	missense	Exon 56 of 63	ENSP00000496036.1
	OTOGL	ENST00000298820.7	TSL:5	c.1525+105A>G		intron	N/A	ENSP00000298820.3

Frequencies

GnomAD3 genomes AF: 0.942 AC: 143322 AN: 152162 Hom.: 67568 Cov.: 32

Gnomad AFR AF: 0.961

Gnomad AMI AF: 0.940

Gnomad AMR AF: 0.941

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.973

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.924

Gnomad OTH AF: 0.934

GnomAD2 exomes AF: 0.941 AC: 139151 AN: 147890 AF XY: 0.939

Gnomad AFR exome AF: 0.962

Gnomad AMR exome AF: 0.957

Gnomad ASJ exome AF: 0.895

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.971

Gnomad NFE exome AF: 0.921

Gnomad OTH exome AF: 0.922

GnomAD4 exome AF: 0.927 AC: 1254466 AN: 1352782 Hom.: 582006 Cov.: 34 AF XY: 0.927 AC XY: 620823 AN XY: 669428

African (AFR) AF: 0.959 AC: 29457 AN: 30702

American (AMR) AF: 0.955 AC: 33933 AN: 35540

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 22271 AN: 24934

East Asian (EAS) AF: 1.00 AC: 35514 AN: 35522

South Asian (SAS) AF: 0.948 AC: 74139 AN: 78174

European-Finnish (FIN) AF: 0.970 AC: 35077 AN: 36152

Middle Eastern (MID) AF: 0.856 AC: 4365 AN: 5098

European-Non Finnish (NFE) AF: 0.921 AC: 966990 AN: 1049896

Other (OTH) AF: 0.929 AC: 52720 AN: 56764

GnomAD4 genome AF: 0.942 AC: 143416 AN: 152280 Hom.: 67607 Cov.: 32 AF XY: 0.944 AC XY: 70315 AN XY: 74452

African (AFR) AF: 0.960 AC: 39919 AN: 41564

American (AMR) AF: 0.941 AC: 14391 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.901 AC: 3128 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5182 AN: 5184

South Asian (SAS) AF: 0.947 AC: 4566 AN: 4822

European-Finnish (FIN) AF: 0.973 AC: 10334 AN: 10622

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.924 AC: 62810 AN: 68006

Other (OTH) AF: 0.935 AC: 1978 AN: 2116

Alfa AF: 0.927 Hom.: 132570

Bravo AF: 0.941

TwinsUK AF: 0.921 AC: 3415

ALSPAC AF: 0.927 AC: 3571

ESP6500AA AF: 0.959 AC: 4160

ESP6500EA AF: 0.924 AC: 7815

ExAC AF: 0.928 AC: 76951

Asia WGS AF: 0.976 AC: 3388 AN: 3472

ClinVar

ClinVar submissions as Germline

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	0.064
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.8
DANN	Benign	0.29
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	6.5e-7	T
MetaSVM	Benign	-0.96	T
PhyloP100		0.55
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.026
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.058
MPC		0.021
ClinPred		0.00015	T
GERP RS		0.35
gMVP		0.26
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2034528; hg19: chr12-80752660; COSMIC: COSV107327498;