rs139767460

chr2-26464041-G-Achr2-26464041-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_194248.3(OTOF):c.5026C>T(p.Arg1676Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000835 in 1,613,656 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1676H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00086 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (18 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.03

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008848131).
• BP6: Variant 2-26464041-G-A is Benign according to our data. Variant chr2-26464041-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26464041-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-26464041-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00086 (131/152282) while in subpopulation EAS AF= 0.0195 (101/5168). AF 95% confidence interval is 0.0165. There are 4 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.5026C>T	p.Arg1676Cys	missense_variant	40/47	ENST00000272371.7
OTOF	NM_194323.3	c.2725C>T	p.Arg909Cys	missense_variant	23/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.5026C>T	p.Arg1676Cys	missense_variant	40/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.2725C>T	p.Arg909Cys	missense_variant	23/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.000867 AC: 132 AN: 152164 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00144 AC: 362 AN: 250878 Hom.: 6 AF XY: 0.00137 AC XY: 186 AN XY: 135746

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0181

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000832 AC: 1216 AN: 1461374 Hom.: 18 Cov.: 32 AF XY: 0.000799 AC XY: 581 AN XY: 727004

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0272

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152282 Hom.: 4 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74462

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0195

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000715 Hom.: 0

Bravo AF: 0.000979

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00134 AC: 163

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is associated with the following publications: (PMID: 21935370, 22575033, 24053799, 28335750, 22906306, 26346818, 30245029, 33095980) -

Autosomal recessive nonsyndromic hearing loss 9 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2022	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 11, 2014

Arg1676Cys in exon 40 of OTOF: This variant has been reported in two individuals with hearing loss (Isawa 2013, Wang 2011) but it is not expected to have clinic al significance because it has been seen in 1.6% (9/572) of Asian chromosomes by the 1000 Genomes Project (dbSNP rs139767460), with the frequency in Japanese ch romosomes in particular being 3.4% (6/178). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.14
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.31	T;T;T;T;T;T
MetaRNN	Benign	0.0088	T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.8	D;D;.;D;D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0090	D;D;.;D;D;.
Sift4G	Uncertain	0.026	D;D;.;D;D;.
Polyphen		0.97	D;D;.;D;.;D
Vest4		0.47
MVP		0.74
MPC		0.55
ClinPred		0.061	T
GERP RS		3.5
Varity_R		0.21
gMVP		0.68

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: rs139767460; hg19: chr2-26686909; COSMIC: COSV55502099;