rs111033393

chr2-26464004-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP3 BP4_Strong BP6

The NM_194248.3(OTOF):c.5063C>T(p.Thr1688Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,613,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1688K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 8.10

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.054777652).
• BP6: Variant 2-26464004-G-A is Benign according to our data. Variant chr2-26464004-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48248.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.5063C>T	p.Thr1688Met	missense_variant	40/47	ENST00000272371.7
OTOF	NM_194323.3	c.2762C>T	p.Thr921Met	missense_variant	23/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.5063C>T	p.Thr1688Met	missense_variant	40/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.2762C>T	p.Thr921Met	missense_variant	23/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00126 AC: 315 AN: 250620 Hom.: 0 AF XY: 0.00133 AC XY: 180 AN XY: 135614

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00143 AC: 2095 AN: 1461474 Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 1004 AN XY: 727044

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000358

Gnomad4 NFE exome AF: 0.00166

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.00117 AC XY: 87 AN XY: 74448

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.00142

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported in association with hearing loss to our knowledge; This variant is associated with the following publications: (PMID: 19461658) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 04, 2019	- -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1 Benign:1

Uncertain significance, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 08, 2012	Thr1688Met in exon 40 of OTOF: This variant has been identified in three individ uals by our laboratory, none of whom had second OTOF variants and one of whom ha d another cause of hearing loss. In addition, this variant has been identified i n 0.19% (16/8600) of European American chromosomes in a broad population by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; dbSNP rs11103 3393). In summary, these data suggest this variant is likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.055	T;T;T;T;T;T
MetaSVM	Pathogenic	0.96	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.4	D;D;.;D;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;D;.;D;D;.
Sift4G	Uncertain	0.0020	D;D;.;D;D;.
Polyphen		0.99	D;D;.;D;.;D
Vest4		0.83
MVP		0.94
MPC		0.60
ClinPred		0.034	T
GERP RS		4.4
Varity_R		0.53
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033393; hg19: chr2-26686872;