NM_001378609.3:c.4860G>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOGL	NM_001378609.3	c.4860G>A	p.Lys1620Lys	splice_region_variant, synonymous_variant	Exon 42 of 59	ENST00000547103.7	NP_001365538.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOGL	ENST00000547103.7	c.4860G>A	p.Lys1620Lys	splice_region_variant, synonymous_variant	Exon 42 of 59	5	NM_001378609.3	ENSP00000447211.2
OTOGL	ENST00000646859.1	c.4725G>A	p.Lys1575Lys	splice_region_variant, synonymous_variant	Exon 46 of 63			ENSP00000496036.1
OTOGL	ENST00000298820.7	c.159G>A	p.Lys53Lys	splice_region_variant, synonymous_variant	Exon 3 of 18	5		ENSP00000298820.3

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

GnomAD3 exomes AF: 0.0000436 AC: 8 AN: 183400 Hom.: 0 AF XY: 0.0000614 AC XY: 6 AN XY: 97706

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000251

Gnomad4 FIN exome AF: 0.0000981

Gnomad4 NFE exome AF: 0.0000240

Gnomad4 OTH exome AF: 0.0000171

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

Gnomad4 AFR AF: 0.0000485

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000965

Gnomad4 NFE AF: 0.0000590

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000711 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys1611Lys variant in OTOGL has been identified in cis with the p.Phe845Leu variant in one individual with hearing loss by our laboratory and has been reported together with p.Phe845Leu in one additional individual with hearing loss (phase unknown; Zazo Seco 2017). The p.Lys1611Lys variant has also been identified in 0.008% (8/90266) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), and has been reported as a variant of uncertain significance in ClinVar (Variation ID 425014). This variant is located in the last base of the exon, which is part of the 5’ splice region. While computational tools do not suggest an impact to splicing, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Lys1611Lys variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, BP4. -

not provided Uncertain:1

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs753442959; hg19: chr12-80730784;