12-80320554-A-T

Variant names:

• chr12-80320554-A-T
• rs768575822
• NM_001378609.3:c.3935A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001378609.3(OTOGL):​c.3935A>T​(p.His1312Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1312Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.65
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

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.3935A>T	p.His1312Leu	missense	Exon 34 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.3935A>T	p.His1312Leu	missense	Exon 37 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.3935A>T	p.His1312Leu	missense	Exon 34 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.3935A>T	p.His1312Leu	missense	Exon 34 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.3800A>T	p.His1267Leu	missense	Exon 38 of 63	ENSP00000496036.1	A0A2R8YF04

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246100 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461336 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726922

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111716

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.98
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-1.0	T
PhyloP100		8.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-9.6	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Vest4		0.86
MutPred		0.83		Loss of disorder (P = 0.1096)
MVP		0.23
MPC		0.20
ClinPred		1.0	D
GERP RS		5.5
gMVP		0.83
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs768575822; hg19: chr12-80714334;