2-26537756-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.98G>A(p.Arg33Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00135 in 1,554,618 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R33W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0067 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (7 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 3.97

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=0.009204447).
• BP6: Variant 2-26537756-C-T is Benign according to our data. Variant chr2-26537756-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48278.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=5, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00675 (1027/152204) while in subpopulation AFR AF= 0.0233 (966/41524). AF 95% confidence interval is 0.022. There are 10 homozygotes in gnomad4. There are 506 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.98G>A	p.Arg33Gln	missense_variant	2/47	ENST00000272371.7
OTOF	NM_001287489.2	c.98G>A	p.Arg33Gln	missense_variant	2/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.98G>A	p.Arg33Gln	missense_variant	2/47	1	NM_194248.3	A1
OTOF	ENST00000403946.7	c.98G>A	p.Arg33Gln	missense_variant	2/46	5		P4

Frequencies

GnomAD3 genomes AF: 0.00673 AC: 1023 AN: 152086 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00195 AC: 315 AN: 161902 Hom.: 2 AF XY: 0.00141 AC XY: 120 AN XY: 85296

Gnomad AFR exome AF: 0.0261

Gnomad AMR exome AF: 0.00224

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000851

Gnomad SAS exome AF: 0.0000870

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.000762 AC: 1068 AN: 1402414 Hom.: 7 Cov.: 30 AF XY: 0.000685 AC XY: 474 AN XY: 692062

Gnomad4 AFR exome AF: 0.0235

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.0000756

Gnomad4 FIN exome AF: 0.0000404

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.00175

GnomAD4 genome AF: 0.00675 AC: 1027 AN: 152204 Hom.: 10 Cov.: 33 AF XY: 0.00680 AC XY: 506 AN XY: 74408

Gnomad4 AFR AF: 0.0233

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00330 Hom.: 2

Bravo AF: 0.00791

ESP6500AA AF: 0.0187 AC: 82

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00124 AC: 136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2019	This variant is associated with the following publications: (PMID: 19461658, 29362361) -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 12, 2011	Arg33Gln in exon 2 of OTOF: This variant has been reported in one study after id entification in a single hearing loss proband (Romanos 2006). However, this vari ant is not expected to have clinical significance because it is present in the d bSNP database (rs56332208) with a frequency of 6.8% (8/118 chromosomes) in the Y RI HapMap population and 1.1% (34/3098) in the ESP North American cohort. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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	Benign	0.093
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.63	N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.022	D;D
Sift4G	Benign	0.11	T;T
Polyphen		1.0	D;.
Vest4		0.63
MVP		0.92
MPC		0.70
ClinPred		0.021	T
GERP RS		4.8
Varity_R		0.23
gMVP		0.45

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: rs56332208; hg19: chr2-26760624;