rs4665855

Positions:

• chr2-26477832-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194322.3(OTOF):​c.62C>T​(p.Pro21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,576,720 control chromosomes in the GnomAD database, including 163,722 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18095 hom., cov: 32)
  • Exomes 𝑓: 0.44 (145627 hom.)
• Consequence: OTOF NM_194322.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.327

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=1.2123064E-6).
• BP6: Variant 2-26477832-G-A is Benign according to our data. Variant chr2-26477832-G-A is described in ClinVar as [Benign]. Clinvar id is 48191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26477832-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2215-83C>T		intron_variant		ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.-28+12C>T		intron_variant		ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2215-83C>T		intron_variant		1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.-28+12C>T		intron_variant		1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71619 AN: 151918 Hom.: 18076 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.440

GnomAD3 exomes AF: 0.524 AC: 101448 AN: 193584 Hom.: 29309 AF XY: 0.516 AC XY: 53561 AN XY: 103792

Gnomad AFR exome AF: 0.458

Gnomad AMR exome AF: 0.688

Gnomad ASJ exome AF: 0.354

Gnomad EAS exome AF: 0.987

Gnomad SAS exome AF: 0.541

Gnomad FIN exome AF: 0.579

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.438 AC: 623898 AN: 1424682 Hom.: 145627 Cov.: 38 AF XY: 0.440 AC XY: 310290 AN XY: 705488

Gnomad4 AFR exome AF: 0.447

Gnomad4 AMR exome AF: 0.670

Gnomad4 ASJ exome AF: 0.355

Gnomad4 EAS exome AF: 0.976

Gnomad4 SAS exome AF: 0.540

Gnomad4 FIN exome AF: 0.564

Gnomad4 NFE exome AF: 0.399

Gnomad4 OTH exome AF: 0.461

GnomAD4 genome AF: 0.471 AC: 71682 AN: 152038 Hom.: 18095 Cov.: 32 AF XY: 0.484 AC XY: 35978 AN XY: 74320

Gnomad4 AFR AF: 0.453

Gnomad4 AMR AF: 0.574

Gnomad4 ASJ AF: 0.359

Gnomad4 EAS AF: 0.984

Gnomad4 SAS AF: 0.564

Gnomad4 FIN AF: 0.594

Gnomad4 NFE AF: 0.402

Gnomad4 OTH AF: 0.445

Alfa AF: 0.425 Hom.: 16065

Bravo AF: 0.471

TwinsUK AF: 0.382 AC: 1415

ALSPAC AF: 0.405 AC: 1560

ESP6500AA AF: 0.440 AC: 1167

ESP6500EA AF: 0.394 AC: 1821

ExAC AF: 0.472 AC: 55243

Asia WGS AF: 0.746 AC: 2589 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro21Leu in exon 1 of OTOF: This variant is not expected to have clinical signif icance because it is has been identified in 5.4% (337/6988) of European American chromosomes and 28.3% (1051/3718) of African American chromosomes from a broad population by the NHLBI Exome sequencing project (http://evs.gs.washington.edu/E VS/; dbSNP rs4665855). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	1.0
DANN	Benign	0.65
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
Polyphen		0.0	B
ClinPred		0.025	T
GERP RS		-0.57

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: rs4665855; hg19: chr2-26700700; COSMIC: COSV55522507; COSMIC: COSV55522507;