2-26473506-C-T

Position:

• chr2-26473506-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_194248.3(OTOF):​c.3470G>A​(p.Arg1157Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,612,842 control chromosomes in the GnomAD database, including 146 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 0.0085 (7 hom., cov: 33)
  • Exomes 𝑓: 0.013 (139 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6 O:1
• Conservation: PhyloP100: 2.76

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0115759075).
• BP6: Variant 2-26473506-C-T is Benign according to our data. Variant chr2-26473506-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21845.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, not_provided=1, Benign=5}. Variant chr2-26473506-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00847 (1290/152238) while in subpopulation NFE AF= 0.0146 (990/68002). AF 95% confidence interval is 0.0138. There are 7 homozygotes in gnomad4. There are 538 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.3470G>A	p.Arg1157Gln	missense_variant	28/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.1229G>A	p.Arg410Gln	missense_variant	11/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.3470G>A	p.Arg1157Gln	missense_variant	28/47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.1229G>A	p.Arg410Gln	missense_variant	11/29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.00849 AC: 1291 AN: 152120 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0146

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00809 AC: 2022 AN: 250062 Hom.: 14 AF XY: 0.00793 AC XY: 1074 AN XY: 135474

Gnomad AFR exome AF: 0.00210

Gnomad AMR exome AF: 0.00955

Gnomad ASJ exome AF: 0.00280

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00146

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0129 AC: 18796 AN: 1460604 Hom.: 139 Cov.: 33 AF XY: 0.0124 AC XY: 9043 AN XY: 726668

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.00352

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000870

Gnomad4 FIN exome AF: 0.00170

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.00847 AC: 1290 AN: 152238 Hom.: 7 Cov.: 33 AF XY: 0.00723 AC XY: 538 AN XY: 74442

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.00974

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.0146

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0112 Hom.: 6

Bravo AF: 0.00954

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0169 AC: 65

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0150 AC: 129

ExAC AF: 0.00798 AC: 969

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0141

EpiControl AF: 0.0149

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 02, 2011	Arg1157Gln in exon 28 of OTOF: This variant is not expected to have clinical sig nificance because it has been identified in 0.7% (50/6794) of chromosomes from a broad population (dbSNP rs56054534). In addition, this variant has been reporte d in the literature and is not expected to have clinical significance due to an equal occurrence in probands and controls (Smith 2008, Varga 2006). -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 20230791, 16371502, 27766948) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	OTOF: BS1, BS2 -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	.;.;.;T;.;.
Eigen	Benign	-0.053
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
MetaRNN	Benign	0.012	T;T;T;T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	-0.99	.;.;.;N;N;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.5	N;N;.;N;N;.
REVEL	Uncertain	0.36
Sift	Benign	1.0	T;T;.;T;T;.
Sift4G	Benign	1.0	T;T;.;T;T;.
Polyphen		0.30	B;P;.;D;.;D
Vest4		0.37
MVP		0.88
MPC		0.71
ClinPred		0.013	T
GERP RS		5.2
Varity_R		0.25
gMVP		0.69

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: rs56054534; hg19: chr2-26696374;