chr12-80210862-C-T

Variant names:

• chr12-80210862-C-T
• rs760011677
• NM_001378609.3:c.95C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001378609.3(OTOGL):​c.95C>T​(p.Ser32Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,472,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.26
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

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.95C>T	p.Ser32Leu	missense	Exon 3 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.95C>T	p.Ser32Leu	missense	Exon 6 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.95C>T	p.Ser32Leu	missense	Exon 3 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.95C>T	p.Ser32Leu	missense	Exon 3 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.95C>T	p.Ser32Leu	missense	Exon 8 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000643417.1		n.755C>T		non_coding_transcript_exon	Exon 6 of 23

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151692 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000127 AC: 14 AN: 109812 AF XY: 0.0000991

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000534

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000225

Gnomad OTH exome AF: 0.000306

GnomAD4 exome AF: 0.000210 AC: 277 AN: 1320688 Hom.: 0 Cov.: 28 AF XY: 0.000198 AC XY: 129 AN XY: 651976

African (AFR) AF: 0.00 AC: 0 AN: 28922

American (AMR) AF: 0.00 AC: 0 AN: 30866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24016

East Asian (EAS) AF: 0.00 AC: 0 AN: 33050

South Asian (SAS) AF: 0.0000703 AC: 5 AN: 71112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32722

Middle Eastern (MID) AF: 0.000362 AC: 2 AN: 5520

European-Non Finnish (NFE) AF: 0.000252 AC: 262 AN: 1039134

Other (OTH) AF: 0.000145 AC: 8 AN: 55346

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151692 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74040

African (AFR) AF: 0.0000242 AC: 1 AN: 41254

American (AMR) AF: 0.0000657 AC: 1 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67936

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.0000687 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 84B (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.21
Eigen	Benign	0.011
Eigen_PC	Benign	0.047
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.061
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0	D
Vest4		0.16
MVP		0.14
MPC		0.026
ClinPred		0.064	T
GERP RS		5.8
gMVP		0.15
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs760011677; hg19: chr12-80604642; COSMIC: COSV108960836;