rs143933877

chr2-26477904-T-Cchr2-26477904-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_194323.3(OTOF):c.-88A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000971 in 1,534,770 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00077 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (22 hom.)
• Consequence: OTOF NM_194323.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.137

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 2-26477904-T-C is Benign according to our data. Variant chr2-26477904-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 179695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194323.3	c.-88A>G		5_prime_UTR_variant	1/29	ENST00000339598.8
OTOF	NM_194248.3	c.2215-155A>G		intron_variant		ENST00000272371.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000339598.8	c.-88A>G		5_prime_UTR_variant	1/29	1	NM_194323.3
OTOF	ENST00000272371.7	c.2215-155A>G		intron_variant		1	NM_194248.3	A1

Frequencies

GnomAD3 genomes AF: 0.000776 AC: 118 AN: 151980 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00206 AC: 299 AN: 145334 Hom.: 1 AF XY: 0.00263 AC XY: 202 AN XY: 76688

Gnomad AFR exome AF: 0.000383

Gnomad AMR exome AF: 0.000527

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000450

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.000994 AC: 1374 AN: 1382672 Hom.: 22 Cov.: 35 AF XY: 0.00133 AC XY: 908 AN XY: 680176

Gnomad4 AFR exome AF: 0.000420

Gnomad4 AMR exome AF: 0.000650

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.0000281

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000257

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.000769 AC: 117 AN: 152098 Hom.: 3 Cov.: 32 AF XY: 0.000996 AC XY: 74 AN XY: 74330

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000755 Hom.: 0

Bravo AF: 0.000487

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 30, 2015

c.-11A>G in intron 1A of OTOF: This variant is not expected to have clinical sig nificance because it has been identified in 1.4% (76/5536) of South Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143933877). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	6.0
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143933877; hg19: chr2-26700772;