2-26457798-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.836

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 -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 GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.*440T>C		3_prime_UTR_variant	47/47	ENST00000272371.7
OTOF	NM_194323.3	c.*242T>C		3_prime_UTR_variant	29/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.*440T>C		3_prime_UTR_variant	47/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.*242T>C		3_prime_UTR_variant	29/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 1236 AN: 151902 Hom.: 15 Cov.: 33

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

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

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

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	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

Other links and lift over

dbSNP: rs112949167; hg19: chr2-26680666;