12-80318586-G-A

Variant names:

• chr12-80318586-G-A
• rs139375212
• NM_001378609.3:c.3675G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001378609.3(OTOGL):​c.3675G>A​(p.Gln1225Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000781 in 1,279,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• 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: 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP7: Synonymous conserved (PhyloP=0.058 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	NM_001378609.3	MANE Select	c.3675G>A	p.Gln1225Gln	synonymous	Exon 33 of 59	NP_001365538.2
	OTOGL	NM_001378610.3		c.3675G>A	p.Gln1225Gln	synonymous	Exon 36 of 62	NP_001365539.2
	OTOGL	NM_173591.7		c.3675G>A	p.Gln1225Gln	synonymous	Exon 33 of 59	NP_775862.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.3675G>A	p.Gln1225Gln	synonymous	Exon 33 of 59	ENSP00000447211.2
	OTOGL	ENST00000646859.1		c.3540G>A	p.Gln1180Gln	synonymous	Exon 37 of 63	ENSP00000496036.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.81e-7 AC: 1 AN: 1279902 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 628190

African (AFR) AF: 0.00 AC: 0 AN: 25880

American (AMR) AF: 0.00 AC: 0 AN: 17624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20590

East Asian (EAS) AF: 0.00 AC: 0 AN: 30948

South Asian (SAS) AF: 0.0000176 AC: 1 AN: 56778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5194

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1025144

Other (OTH) AF: 0.00 AC: 0 AN: 52238

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.1
DANN	Benign	0.56
PhyloP100		0.058

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs139375212; hg19: chr12-80712366; COSMIC: COSV106602810;