rs41286009

Variant names:

• chr2-26465040-G-A
• rs41286009
• NM_194248.3:c.4800-11C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26465040-G-A
• chr2-26465040-G-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.4800-11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,463,404 control chromosomes in the GnomAD database, including 8 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 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: OTOF NM_194248.3 intron
• Scores: Splicing: ADA: 0.00002085
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.191
• 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=-0.82).
• BP6: Variant 2-26465040-G-A is Benign according to our data. Variant chr2-26465040-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178505.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00175 (266/152206) while in subpopulation NFE AF = 0.00294 (200/67996). AF 95% confidence interval is 0.00261. There are 0 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.4800-11C>T		intron_variant	Intron 38 of 46	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.2499-11C>T		intron_variant	Intron 21 of 28	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.4800-11C>T		intron_variant	Intron 38 of 46	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.2499-11C>T		intron_variant	Intron 21 of 28	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152088 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00184 AC: 291 AN: 158126 AF XY: 0.00189

Gnomad AFR exome AF: 0.000245

Gnomad AMR exome AF: 0.000577

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000779

Gnomad FIN exome AF: 0.000585

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.00239

GnomAD4 exome AF: 0.00267 AC: 3507 AN: 1311198 Hom.: 8 Cov.: 31 AF XY: 0.00273 AC XY: 1743 AN XY: 638610

African (AFR) AF: 0.000361 AC: 10 AN: 27728

American (AMR) AF: 0.000483 AC: 14 AN: 29004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35406

South Asian (SAS) AF: 0.00274 AC: 162 AN: 59130

European-Finnish (FIN) AF: 0.000555 AC: 27 AN: 48658

Middle Eastern (MID) AF: 0.00291 AC: 15 AN: 5148

European-Non Finnish (NFE) AF: 0.00306 AC: 3167 AN: 1033302

Other (OTH) AF: 0.00209 AC: 112 AN: 53644

GnomAD4 genome AF: 0.00175 AC: 266 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.00172 AC XY: 128 AN XY: 74408

African (AFR) AF: 0.000554 AC: 23 AN: 41520

American (AMR) AF: 0.00163 AC: 25 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5162

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00294 AC: 200 AN: 67996

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00262 Hom.: 0

Bravo AF: 0.00169

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Jul 31, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

Jan 13, 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. -

not specified Benign:1

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

4800-11C>T in Intron 38 of OTOF: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (23/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs41286009). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.3
DANN	Benign	0.70
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs41286009; hg19: chr2-26687908;