rs76130130

Positions:

• chr2-26477826-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_194322.3(OTOF):​c.68T>G​(p.Ile23Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,587,232 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (36 hom.)
• Consequence: OTOF NM_194322.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.168

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004008025).
• BP6: Variant 2-26477826-A-C is Benign according to our data. Variant chr2-26477826-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 48190.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26477826-A-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.2215-77T>G		intron_variant		ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.-28+18T>G		intron_variant		ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.2215-77T>G		intron_variant		1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.-28+18T>G		intron_variant		1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 519 AN: 152096 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00487

Gnomad OTH AF: 0.00817

GnomAD3 exomes AF: 0.00430 AC: 866 AN: 201304 Hom.: 6 AF XY: 0.00414 AC XY: 448 AN XY: 108272

Gnomad AFR exome AF: 0.000663

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000793

Gnomad FIN exome AF: 0.000207

Gnomad NFE exome AF: 0.00604

Gnomad OTH exome AF: 0.00708

GnomAD4 exome AF: 0.00535 AC: 7682 AN: 1435018 Hom.: 36 Cov.: 34 AF XY: 0.00517 AC XY: 3677 AN XY: 711602

Gnomad4 AFR exome AF: 0.000854

Gnomad4 AMR exome AF: 0.00537

Gnomad4 ASJ exome AF: 0.0156

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000805

Gnomad4 FIN exome AF: 0.000257

Gnomad4 NFE exome AF: 0.00602

Gnomad4 OTH exome AF: 0.00518

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152214 Hom.: 1 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74424

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00487

Gnomad4 OTH AF: 0.00808

Alfa AF: 0.00556 Hom.: 5

Bravo AF: 0.00395

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00113 AC: 3

ESP6500EA AF: 0.00542 AC: 25

ExAC AF: 0.00362 AC: 430

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 05, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	OTOF: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Ile23Ser in Exon 01 of OTOF: This variant is not expected to have clinical signi ficance because it has been identified in 0.5% (22/4104) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs76130130). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	1.0
DANN	Benign	0.94
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.99	T
Polyphen		0.0010	B
ClinPred		0.060	T
GERP RS		-4.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs76130130; hg19: chr2-26700694;