2-26472659-T-G

Variant names:

• chr2-26472659-T-G
• rs73920284
• NM_194248.3:c.3734-10A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_194248.3(OTOF):​c.3734-10A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000487 in 1,612,350 control chromosomes in the GnomAD database, including 5 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 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (3 hom.)
• Consequence: OTOF NM_194248.3 intron
• Scores: Splicing: ADA: 0.000006609
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.609
• Publications: 0 publications found

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]

OTOF Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-26472659-T-G is Benign according to our data. Variant chr2-26472659-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48223.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00277 (422/152148) while in subpopulation AFR AF = 0.00993 (412/41488). AF 95% confidence interval is 0.00914. There are 2 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.3734-10A>C		intron_variant	Intron 29 of 46	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.1493-70A>C		intron_variant	Intron 12 of 28	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.3734-10A>C		intron_variant	Intron 29 of 46	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.1493-70A>C		intron_variant	Intron 12 of 28	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.00278 AC: 422 AN: 152030 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00996

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000693 AC: 172 AN: 248122 AF XY: 0.000483

Gnomad AFR exome AF: 0.00967

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.000249 AC: 363 AN: 1460202 Hom.: 3 Cov.: 32 AF XY: 0.000194 AC XY: 141 AN XY: 726328

African (AFR) AF: 0.00932 AC: 312 AN: 33474

American (AMR) AF: 0.000359 AC: 16 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52332

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111690

Other (OTH) AF: 0.000480 AC: 29 AN: 60354

GnomAD4 genome AF: 0.00277 AC: 422 AN: 152148 Hom.: 2 Cov.: 33 AF XY: 0.00298 AC XY: 222 AN XY: 74390

African (AFR) AF: 0.00993 AC: 412 AN: 41488

American (AMR) AF: 0.000523 AC: 8 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00301

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Feb 26, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.3734-10A>C in intron 30 of OTOF: This variant is not expected to have clinical significance because it has been identified in 1.1% (106/9424) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs73920284). -

not provided Benign:2

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.56
PhyloP100		0.61
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000066
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs73920284; hg19: chr2-26695527;