rs876657560

Variant names:

• chr12-80267241-T-C
• rs876657560
• NM_001378609.3:c.2391-12T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001378609.3(OTOGL):​c.2391-12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,343,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: OTOGL NM_001378609.3 intron
• Scores: Splicing: ADA: 0.0001715
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.58
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-80267241-T-C is Benign according to our data. Variant chr12-80267241-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 227814.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2391-12T>C		intron	N/A	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.2391-12T>C		intron	N/A	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.2391-12T>C		intron	N/A	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.2391-12T>C		intron	N/A	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.2391-12T>C		intron	N/A	ENSP00000496036.1	A0A2R8YF04

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1343708 Hom.: 0 Cov.: 27 AF XY: 0.00000300 AC XY: 2 AN XY: 666794

African (AFR) AF: 0.00 AC: 0 AN: 30182

American (AMR) AF: 0.00 AC: 0 AN: 36166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24352

East Asian (EAS) AF: 0.00 AC: 0 AN: 36604

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5532

European-Non Finnish (NFE) AF: 9.72e-7 AC: 1 AN: 1028300

Other (OTH) AF: 0.00 AC: 0 AN: 56032

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.7
DANN	Benign	0.42
PhyloP100		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.0040
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: rs876657560; hg19: chr12-80661021;