rs55676840

chr2-26480866-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_194248.3(OTOF):c.1723G>A(p.Val575Met) variant causes a missense change. The variant allele was found at a frequency of 0.012 in 1,613,016 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V575A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0089 (17 hom., cov: 33)
  • Exomes 𝑓: 0.012 (177 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign reviewed by expert panel B:8 O:1
• Conservation: PhyloP100: 5.00

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007778913).
• BP6: Variant 2-26480866-C-T is Benign according to our data. Variant chr2-26480866-C-T is described in ClinVar as [Benign]. Clinvar id is 21826.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00886 (1349/152282) while in subpopulation SAS AF= 0.0433 (209/4824). AF 95% confidence interval is 0.0385. There are 17 homozygotes in gnomad4. There are 683 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.1723G>A	p.Val575Met	missense_variant	15/47	ENST00000272371.7
OTOF	NM_001287489.2	c.1723G>A	p.Val575Met	missense_variant	15/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.1723G>A	p.Val575Met	missense_variant	15/47	1	NM_194248.3	A1
OTOF	ENST00000403946.7	c.1723G>A	p.Val575Met	missense_variant	15/46	5		P4

Frequencies

GnomAD3 genomes AF: 0.00887 AC: 1350 AN: 152164 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0435

Gnomad FIN AF: 0.00847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0121 AC: 3025 AN: 249328 Hom.: 49 AF XY: 0.0134 AC XY: 1819 AN XY: 135344

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00260

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0415

Gnomad FIN exome AF: 0.00944

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.0123

GnomAD4 exome AF: 0.0123 AC: 18023 AN: 1460734 Hom.: 177 Cov.: 33 AF XY: 0.0131 AC XY: 9526 AN XY: 726646

Gnomad4 AFR exome AF: 0.00191

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0378

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.00886 AC: 1349 AN: 152282 Hom.: 17 Cov.: 33 AF XY: 0.00917 AC XY: 683 AN XY: 74456

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0433

Gnomad4 FIN AF: 0.00847

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.0108 Hom.: 15

Bravo AF: 0.00778

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.0130 AC: 1577

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.00900

EpiControl AF: 0.00972

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 09, 2011	Val575Met in exon 15 of OTOF: This variant is not expected to have clinical sign ificance because it has been reported as a neutral change (Varga 2006, Smith 200 8), is present in dbSNP (rs55676840 ? 4 entries), adn has been identified in our laboratory in ~3% of patients. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2022	- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
not provided, no classification provided	literature only	GeneReviews	-	- -

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 1269/30610) of the c.1723G>A (p.Val575Met) variant in the OTOF gene is 3.95% for South Asian chromosome in gnomAD v2.1.1, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.28	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.80	P;.
Vest4		0.45
MPC		0.26
ClinPred		0.077	T
GERP RS		4.5
Varity_R		0.26
gMVP		0.76

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: rs55676840; hg19: chr2-26703734; COSMIC: COSV55506444; COSMIC: COSV55506444;