2-26457866-G-A

Variant names:

• chr2-26457866-G-A
• rs56025829
• NM_194248.3:c.*372C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_194248.3(OTOF):​c.*372C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 664,794 control chromosomes in the GnomAD database, including 496 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.039 (353 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (143 hom.)
• Consequence: OTOF NM_194248.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.598
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.*372C>T		3_prime_UTR_variant	Exon 47 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.*174C>T		3_prime_UTR_variant	Exon 29 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.*372C>T		3_prime_UTR_variant	Exon 47 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.*174C>T		3_prime_UTR_variant	Exon 29 of 29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5850 AN: 151918 Hom.: 353 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.0273

GnomAD4 exome AF: 0.00614 AC: 3148 AN: 512758 Hom.: 143 Cov.: 6 AF XY: 0.00525 AC XY: 1423 AN XY: 271250

African (AFR) AF: 0.132 AC: 1871 AN: 14160

American (AMR) AF: 0.0127 AC: 277 AN: 21740

Ashkenazi Jewish (ASJ) AF: 0.000213 AC: 3 AN: 14060

East Asian (EAS) AF: 0.00 AC: 0 AN: 32722

South Asian (SAS) AF: 0.000432 AC: 21 AN: 48586

European-Finnish (FIN) AF: 0.000999 AC: 31 AN: 31040

Middle Eastern (MID) AF: 0.0131 AC: 27 AN: 2054

European-Non Finnish (NFE) AF: 0.00166 AC: 533 AN: 320338

Other (OTH) AF: 0.0137 AC: 385 AN: 28058

GnomAD4 genome AF: 0.0386 AC: 5862 AN: 152036 Hom.: 353 Cov.: 32 AF XY: 0.0364 AC XY: 2705 AN XY: 74330

African (AFR) AF: 0.130 AC: 5372 AN: 41414

American (AMR) AF: 0.0205 AC: 314 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10606

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 67992

Other (OTH) AF: 0.0270 AC: 57 AN: 2108

Alfa AF: 0.00489 Hom.: 4

Bravo AF: 0.0441

Asia WGS AF: 0.00722 AC: 26 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.51
PhyloP100		-0.60
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56025829; hg19: chr2-26680734; COSMIC: COSV55503401; COSMIC: COSV55503401;