rs117985483

chr2-26519100-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_194248.3(OTOF):c.237G>A(p.Gly79=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,597,790 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (4 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.477

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 2-26519100-C-T is Benign according to our data. Variant chr2-26519100-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48195.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=0.477 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.237G>A	p.Gly79=	synonymous_variant	4/47	ENST00000272371.7
OTOF	NM_001287489.2	c.237G>A	p.Gly79=	synonymous_variant	4/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.237G>A	p.Gly79=	synonymous_variant	4/47	1	NM_194248.3	A1
OTOF	ENST00000403946.7	c.237G>A	p.Gly79=	synonymous_variant	4/46	5		P4

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00751

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000938 AC: 214 AN: 228040 Hom.: 1 AF XY: 0.000951 AC XY: 117 AN XY: 123012

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000213

Gnomad EAS exome AF: 0.00415

Gnomad SAS exome AF: 0.000670

Gnomad FIN exome AF: 0.00523

Gnomad NFE exome AF: 0.000131

Gnomad OTH exome AF: 0.000351

GnomAD4 exome AF: 0.000460 AC: 665 AN: 1445468 Hom.: 4 Cov.: 32 AF XY: 0.000461 AC XY: 331 AN XY: 717816

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000546

Gnomad4 EAS exome AF: 0.00415

Gnomad4 SAS exome AF: 0.000972

Gnomad4 FIN exome AF: 0.00532

Gnomad4 NFE exome AF: 0.0000817

Gnomad4 OTH exome AF: 0.000553

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74478

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00753

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000400

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	This variant is associated with the following publications: (PMID: 20224275) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	OTOF: BP4, BP7 -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain: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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Gly79Gly in Exon 04 of OTOF: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 1/7018 European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs117985483). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	9.5
Dann	Benign	0.62

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: rs117985483; hg19: chr2-26741968;