rs145239283

chr2-26475409-T-A

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.3076A>T(p.Arg1026Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,613,156 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.79

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=0.008550972).
• BP6: Variant 2-26475409-T-A is Benign according to our data. Variant chr2-26475409-T-A is described in ClinVar as [Benign]. Clinvar id is 48213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00409 (622/152246) while in subpopulation AFR AF= 0.013 (539/41534). AF 95% confidence interval is 0.0121. There are 6 homozygotes in gnomad4. There are 295 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.3076A>T	p.Arg1026Trp	missense_variant	25/47	ENST00000272371.7
OTOF	NM_194323.3	c.835A>T	p.Arg279Trp	missense_variant	8/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.3076A>T	p.Arg1026Trp	missense_variant	25/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.835A>T	p.Arg279Trp	missense_variant	8/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 623 AN: 152128 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00100 AC: 252 AN: 250748 Hom.: 3 AF XY: 0.000773 AC XY: 105 AN XY: 135822

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000342 AC: 499 AN: 1460910 Hom.: 4 Cov.: 32 AF XY: 0.000292 AC XY: 212 AN XY: 726768

Gnomad4 AFR exome AF: 0.0107

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000894

GnomAD4 genome AF: 0.00409 AC: 622 AN: 152246 Hom.: 6 Cov.: 32 AF XY: 0.00396 AC XY: 295 AN XY: 74438

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00114 Hom.: 1

Bravo AF: 0.00463

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00128 AC: 155

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 25, 2011

Arg1026Trp in exon 25 of OTOF: This variant is not expected to have clinical sig nificance because it has been identified in dbSNP in 0.4% (18/4544) of control c hromosomes (rs145239283). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	0.079
Eigen_PC	Benign	-0.019
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
MetaRNN	Benign	0.0086	T;T;T;T;T;T
MetaSVM	Uncertain	0.085	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.0	D;D;.;D;D;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0060	D;D;.;D;D;.
Sift4G	Uncertain	0.011	D;D;.;D;D;.
Polyphen		1.0	D;D;.;D;.;D
Vest4		0.74
MVP		0.93
MPC		0.67
ClinPred		0.036	T
GERP RS		2.8
Varity_R		0.45
gMVP		0.64

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: rs145239283; hg19: chr2-26698277;