rs61744348

Positions:

• chr2-26516422-G-A
• chr2-26516422-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_194248.3(OTOF):​c.505C>T​(p.Arg169Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,613,680 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (14 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.34

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008627802).
• BP6: Variant 2-26516422-G-A is Benign according to our data. Variant chr2-26516422-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48247.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4}. Variant chr2-26516422-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00655 (998/152276) while in subpopulation AFR AF= 0.0218 (904/41534). AF 95% confidence interval is 0.0206. There are 16 homozygotes in gnomad4. There are 454 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.505C>T	p.Arg169Trp	missense_variant	5/47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.505C>T	p.Arg169Trp	missense_variant	5/46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.505C>T	p.Arg169Trp	missense_variant	5/47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.505C>T	p.Arg169Trp	missense_variant	5/46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes AF: 0.00655 AC: 996 AN: 152158 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00193 AC: 485 AN: 250940 Hom.: 6 AF XY: 0.00150 AC XY: 203 AN XY: 135658

Gnomad AFR exome AF: 0.0230

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000929 AC: 1357 AN: 1461404 Hom.: 14 Cov.: 33 AF XY: 0.000799 AC XY: 581 AN XY: 726986

Gnomad4 AFR exome AF: 0.0253

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.000613

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00655 AC: 998 AN: 152276 Hom.: 16 Cov.: 32 AF XY: 0.00610 AC XY: 454 AN XY: 74454

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000692 Hom.: 1

Bravo AF: 0.00736

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00226 AC: 274

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2019	This variant is associated with the following publications: (PMID: 31152317) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	OTOF: BS1, BS2 -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 07, 2013

Arg169Trp in exon 5A of OTOF: This variant is not expected to have clinical sign ificance because it has been identified in 2.1% (93/4406) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/; dbSNP rs61744348). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0086	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.67
MVP		0.95
MPC		0.62
ClinPred		0.033	T
GERP RS		5.5
Varity_R		0.36
gMVP		0.42

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: rs61744348; hg19: chr2-26739290;