chr12-80337004-G-A

Variant names:

• chr12-80337004-G-A
• rs753442959
• NM_001378609.3:c.4860G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001378609.3(OTOGL):​c.4860G>A​(p.Lys1620Lys) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000263 in 1,561,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: OTOGL NM_001378609.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9947
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.39
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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.4860G>A	p.Lys1620Lys	splice_region synonymous	Exon 42 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.4860G>A	p.Lys1620Lys	splice_region synonymous	Exon 45 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.4860G>A	p.Lys1620Lys	splice_region synonymous	Exon 42 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.4860G>A	p.Lys1620Lys	splice_region synonymous	Exon 42 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.4725G>A	p.Lys1575Lys	splice_region synonymous	Exon 46 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.159G>A	p.Lys53Lys	splice_region synonymous	Exon 3 of 18	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.0000463 AC: 7 AN: 151294 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000965

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000436 AC: 8 AN: 183400 AF XY: 0.0000614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000537

Gnomad NFE exome AF: 0.0000934

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000241 AC: 34 AN: 1410206 Hom.: 0 Cov.: 31 AF XY: 0.0000258 AC XY: 18 AN XY: 697830

African (AFR) AF: 0.00 AC: 0 AN: 32156

American (AMR) AF: 0.00 AC: 0 AN: 38902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 37988

South Asian (SAS) AF: 0.0000251 AC: 2 AN: 79670

European-Finnish (FIN) AF: 0.0000981 AC: 5 AN: 50972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.0000240 AC: 26 AN: 1081180

Other (OTH) AF: 0.0000171 AC: 1 AN: 58508

GnomAD4 genome AF: 0.0000463 AC: 7 AN: 151294 Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2 AN XY: 73844

African (AFR) AF: 0.0000485 AC: 2 AN: 41220

American (AMR) AF: 0.00 AC: 0 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

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

European-Finnish (FIN) AF: 0.0000965 AC: 1 AN: 10368

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

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67784

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000711 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.88
PhyloP100		5.4
PromoterAI		-0.067	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.43		Position offset: 0

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

Other links and lift over

dbSNP: rs753442959; hg19: chr12-80730784;