rs75624587

Positions:

• chr2-26477421-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 10P and 16B. PVS1 PP3_Moderate BP6_Very_Strong BA1

The NM_194248.3(OTOF):​c.2401G>T​(p.Glu801Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00657 in 1,586,870 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.033 (265 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (270 hom.)
• Consequence: OTOF NM_194248.3 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.86

Genes affected

OTOF (HGNC:8515): (otoferlin) Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. The short form of the encoded protein has 3 C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has 6 C2 domains. The homology suggests that this protein may be involved in vesicle membrane fusion. Several transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 2-26477421-C-A is Benign according to our data. Variant chr2-26477421-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 335447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2401G>T	p.Glu801Ter	stop_gained	20/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.160G>T	p.Glu54Ter	stop_gained	3/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2401G>T	p.Glu801Ter	stop_gained	20/47	1	NM_194248.3	ENSP00000272371	A1
OTOF	ENST00000339598.8	c.160G>T	p.Glu54Ter	stop_gained	3/29	1	NM_194323.3	ENSP00000344521

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 5000 AN: 152140 Hom.: 264 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.0205

GnomAD3 exomes AF: 0.00855 AC: 1762 AN: 206140 Hom.: 92 AF XY: 0.00619 AC XY: 685 AN XY: 110670

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.00657

Gnomad ASJ exome AF: 0.000327

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000231

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000678

Gnomad OTH exome AF: 0.00496

GnomAD4 exome AF: 0.00377 AC: 5411 AN: 1434612 Hom.: 270 Cov.: 33 AF XY: 0.00322 AC XY: 2287 AN XY: 710830

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.00774

Gnomad4 ASJ exome AF: 0.000195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000304

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000367

Gnomad4 OTH exome AF: 0.00877

GnomAD4 genome AF: 0.0329 AC: 5013 AN: 152258 Hom.: 265 Cov.: 32 AF XY: 0.0321 AC XY: 2392 AN XY: 74450

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000661

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0165 Hom.: 67

Bravo AF: 0.0388

ESP6500AA AF: 0.102 AC: 441

ESP6500EA AF: 0.000700 AC: 6

ExAC AF: 0.00944 AC: 1132

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: OTOF c.2401G>T (p.Glu801X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.012 in 237518 control chromosomes, predominantly at a frequency of 0.12 within the African or African-American subpopulation in the gnomAD database, including 139 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 107 fold of the estimated maximal expected allele frequency for a pathogenic variant in OTOF causing Nonsyndromic Hearing Loss And Deafness, Type 9 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2401G>T in individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 9 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign and likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 18, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	58
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.89
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.91		Position offset: 2
DS_DL_spliceai		0.20		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs75624587; hg19: chr2-26700289;