rs111033366

chr2-26461835-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_194248.3(OTOF):c.5394C>T(p.Asp1798=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,614,200 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 3.44

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-26461835-G-A is Benign according to our data. Variant chr2-26461835-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48260.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=2}.
• BP7: Synonymous conserved (PhyloP=3.44 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.5394C>T	p.Asp1798=	synonymous_variant	43/47	ENST00000272371.7
OTOF	NM_194323.3	c.3093C>T	p.Asp1031=	synonymous_variant	26/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.5394C>T	p.Asp1798=	synonymous_variant	43/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.3093C>T	p.Asp1031=	synonymous_variant	26/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000286 AC: 72 AN: 251488 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135916

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000978 AC: 143 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.0000894 AC XY: 65 AN XY: 727248

Gnomad4 AFR exome AF: 0.00352

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74476

Gnomad4 AFR AF: 0.00298

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000556 Hom.: 0

Bravo AF: 0.000963

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 29, 2021	PM5_Supporting, PM2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 29, 2014

p.Asp1798Asp in exon 43 of OTOF: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 0.4% (40/10584) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs111033366). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	9.8
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111033366; hg19: chr2-26684703;