rs4416176

Variant names:

• chr2-26459778-T-C
• rs4416176
• NM_194248.3:c.*17+230A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_194248.3(OTOF):​c.*17+230A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 152,228 control chromosomes in the GnomAD database, including 2,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.12 (2231 hom., cov: 33)
• Consequence: OTOF NM_194248.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.71
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-26459778-T-C is Benign according to our data. Variant chr2-26459778-T-C is described in ClinVar as Benign. ClinVar VariationId is 1223306.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.*17+230A>G		intron_variant	Intron 46 of 46	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.3512+869A>G		intron_variant	Intron 28 of 28	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.*17+230A>G		intron_variant	Intron 46 of 46	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.3512+869A>G		intron_variant	Intron 28 of 28	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17971 AN: 152110 Hom.: 2220 Cov.: 33

Gnomad AFR AF: 0.0565

Gnomad AMI AF: 0.0780

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.0757

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.0707

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0934

Gnomad OTH AF: 0.106

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.118 AC: 17990 AN: 152228 Hom.: 2231 Cov.: 33 AF XY: 0.121 AC XY: 9031 AN XY: 74442

African (AFR) AF: 0.0565 AC: 2347 AN: 41538

American (AMR) AF: 0.265 AC: 4054 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0757 AC: 263 AN: 3472

East Asian (EAS) AF: 0.639 AC: 3300 AN: 5162

South Asian (SAS) AF: 0.127 AC: 613 AN: 4824

European-Finnish (FIN) AF: 0.0707 AC: 750 AN: 10614

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0934 AC: 6351 AN: 68012

Other (OTH) AF: 0.105 AC: 223 AN: 2114

Alfa AF: 0.111 Hom.: 1928

Bravo AF: 0.136

Asia WGS AF: 0.273 AC: 950 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.23
DANN	Benign	0.73
PhyloP100		-1.7
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: rs4416176; hg19: chr2-26682646;