chr2-26457798-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_194248.3(OTOF):​c.*440T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 528,978 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0081 ( 15 hom., cov: 33)
Exomes 𝑓: 0.0020 ( 6 hom. )

Consequence

OTOF
NM_194248.3 3_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.836
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00814 (1238/152020) while in subpopulation AFR AF= 0.0259 (1072/41466). AF 95% confidence interval is 0.0246. There are 15 homozygotes in gnomad4. There are 572 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
OTOFNM_194248.3 linkuse as main transcriptc.*440T>C 3_prime_UTR_variant 47/47 ENST00000272371.7
OTOFNM_194323.3 linkuse as main transcriptc.*242T>C 3_prime_UTR_variant 29/29 ENST00000339598.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
OTOFENST00000272371.7 linkuse as main transcriptc.*440T>C 3_prime_UTR_variant 47/471 NM_194248.3 A1Q9HC10-1
OTOFENST00000339598.8 linkuse as main transcriptc.*242T>C 3_prime_UTR_variant 29/291 NM_194323.3 Q9HC10-2

Frequencies

GnomAD3 genomes
AF:
0.00814
AC:
1236
AN:
151902
Hom.:
15
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0259
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00491
Gnomad ASJ
AF:
0.000578
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.00107
Gnomad OTH
AF:
0.00576
GnomAD4 exome
AF:
0.00199
AC:
751
AN:
376958
Hom.:
6
Cov.:
3
AF XY:
0.00182
AC XY:
357
AN XY:
196622
show subpopulations
Gnomad4 AFR exome
AF:
0.0265
Gnomad4 AMR exome
AF:
0.00392
Gnomad4 ASJ exome
AF:
0.000251
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000231
Gnomad4 FIN exome
AF:
0.0000411
Gnomad4 NFE exome
AF:
0.00121
Gnomad4 OTH exome
AF:
0.00433
GnomAD4 genome
AF:
0.00814
AC:
1238
AN:
152020
Hom.:
15
Cov.:
33
AF XY:
0.00770
AC XY:
572
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.0259
Gnomad4 AMR
AF:
0.00491
Gnomad4 ASJ
AF:
0.000578
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00106
Gnomad4 OTH
AF:
0.00570
Alfa
AF:
0.00582
Hom.:
3
Bravo
AF:
0.00933
Asia WGS
AF:
0.00202
AC:
8
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
2.4
DANN
Benign
0.74

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs112949167; hg19: chr2-26680666; API