rs114260271

Positions:

• chr2-26481015-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 232/24628) of the c.1580-6C>T variant in the OTOF gene is 0.843% for African/African-American chromosomes by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, splice prediction analysis using MaxEntScan and SpliceAI does not suggest an impact to splicing (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA177561/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (4 hom.)
• Consequence: OTOF NM_194248.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00007058
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: 0.441

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.1580-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000272371.7
OTOF	NM_001287489.2	c.1580-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.1580-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_194248.3	A1
OTOF	ENST00000403946.7	c.1580-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		P4

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 437 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000758 AC: 187 AN: 246818 Hom.: 2 AF XY: 0.000589 AC XY: 79 AN XY: 134194

Gnomad AFR exome AF: 0.00948

Gnomad AMR exome AF: 0.000959

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000283 AC: 412 AN: 1457396 Hom.: 4 Cov.: 32 AF XY: 0.000250 AC XY: 181 AN XY: 725122

Gnomad4 AFR exome AF: 0.00934

Gnomad4 AMR exome AF: 0.000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000830

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152322 Hom.: 1 Cov.: 33 AF XY: 0.00286 AC XY: 213 AN XY: 74478

Gnomad4 AFR AF: 0.00972

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00298

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

1580-6C>T in Intron 14 of OTOF: This variant is not expected to have clinical si gnificance because it has been identified in 0.7% (25/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs114260271). -

Nonsyndromic genetic hearing loss Benign:1

Benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

May 13, 2022

The filtering allele frequency (the lower threshold of the 95% CI of 232/24628) of the c.1580-6C>T variant in the OTOF gene is 0.843% for African/African-American chromosomes by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, splice prediction analysis using MaxEntScan and SpliceAI does not suggest an impact to splicing (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.1
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
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

Publications

LitVar

Other links and lift over

dbSNP: rs114260271; hg19: chr2-26703883;