rs1555298321

Variant names:

• chr12-80329083-A-G
• rs1555298321
• NM_001378609.3:c.4312A>G

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.4312A>G​(p.Met1438Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.335
• 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 (MetaRNN=0.06343886).
• BP6: Variant 12-80329083-A-G is Benign according to our data. Variant chr12-80329083-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 506022.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.4312A>G	p.Met1438Val	missense	Exon 37 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.4312A>G	p.Met1438Val	missense	Exon 40 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.4312A>G	p.Met1438Val	missense	Exon 37 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.4312A>G	p.Met1438Val	missense	Exon 37 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.4177A>G	p.Met1393Val	missense	Exon 41 of 63	ENSP00000496036.1	A0A2R8YF04

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408878 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 699316

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30642

American (AMR) AF: 0.00 AC: 0 AN: 30414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22696

East Asian (EAS) AF: 0.00 AC: 0 AN: 38810

South Asian (SAS) AF: 0.00 AC: 0 AN: 76034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1094906

Other (OTH) AF: 0.00 AC: 0 AN: 58036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

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
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.17
DANN	Benign	0.36
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.34
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.0080
Sift	Benign	0.50	T
Sift4G	Benign	0.70	T
Vest4		0.073
MutPred		0.37		Gain of catalytic residue at M1429 (P = 0.0032)
MVP		0.030
MPC		0.022
ClinPred		0.048	T
GERP RS		-0.93
gMVP		0.36
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1555298321; hg19: chr12-80722863;