rs80356570

chr2-26477231-G-Achr2-26477231-G-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.2464C>T(p.Arg822Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,609,140 control chromosomes in the GnomAD database, including 374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R822Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (20 hom., cov: 32)
  • Exomes 𝑓: 0.019 (354 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 2.12

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=0.008108318).
• BP6: Variant 2-26477231-G-A is Benign according to our data. Variant chr2-26477231-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 21837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26477231-G-A is described in Lovd as [Benign]. Variant chr2-26477231-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0146 (2230/152286) while in subpopulation NFE AF= 0.0195 (1325/68000). AF 95% confidence interval is 0.0186. There are 20 homozygotes in gnomad4. There are 1020 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.2464C>T	p.Arg822Trp	missense_variant	21/47	ENST00000272371.7
OTOF	NM_194323.3	c.223C>T	p.Arg75Trp	missense_variant	4/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.2464C>T	p.Arg822Trp	missense_variant	21/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.223C>T	p.Arg75Trp	missense_variant	4/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2228 AN: 152170 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00890

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0144 AC: 3473 AN: 241134 Hom.: 30 AF XY: 0.0147 AC XY: 1927 AN XY: 131210

Gnomad AFR exome AF: 0.00924

Gnomad AMR exome AF: 0.00742

Gnomad ASJ exome AF: 0.0214

Gnomad EAS exome AF: 0.000166

Gnomad SAS exome AF: 0.00305

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0195 AC: 28407 AN: 1456854 Hom.: 354 Cov.: 33 AF XY: 0.0189 AC XY: 13727 AN XY: 724436

Gnomad4 AFR exome AF: 0.00834

Gnomad4 AMR exome AF: 0.00790

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00323

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.0223

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0146 AC: 2230 AN: 152286 Hom.: 20 Cov.: 32 AF XY: 0.0137 AC XY: 1020 AN XY: 74476

Gnomad4 AFR AF: 0.00895

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0200

Gnomad4 NFE AF: 0.0195

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0175 Hom.: 31

Bravo AF: 0.0143

TwinsUK AF: 0.0254 AC: 94

ALSPAC AF: 0.0202 AC: 78

ESP6500AA AF: 0.00985 AC: 43

ESP6500EA AF: 0.0231 AC: 198

ExAC AF: 0.0141 AC: 1699

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	OTOF: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2018	This variant is associated with the following publications: (PMID: 16371502, 18381613, 16283880, 27884173, 27535533, 19461658, 30245029) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 19, 2008	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2015	- -

Autosomal recessive nonsyndromic hearing loss 9 Benign:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 18, 2022	- -
Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Arg822Trp variant in OTOF has been identified in 2 siblings from 1 family with non-syndromic deafness (PMID: 16283880). However, these affected individuals were also homozygous for a nonsense variant in OTOF and this variant was also present in unaffected individuals (PMID: 16283880). This variant has also been identified in >2% of European (Finnish) chromosomes and 18 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-syndromic deafness. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
MetaRNN	Benign	0.0081	T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.2	D;D;.;D;D;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;D;.;D;D;.
Sift4G	Pathogenic	0.0010	D;D;.;D;D;.
Polyphen		1.0	D;D;.;D;.;D
Vest4		0.47
MPC		0.59
ClinPred		0.037	T
GERP RS		2.9
Varity_R		0.43
gMVP		0.55

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: rs80356570; hg19: chr2-26700099; COSMIC: COSV55516101; COSMIC: COSV55516101;