rs11893228

Positions:

• chr2-26464028-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_194248.3(OTOF):​c.5039G>A​(p.Arg1680His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,613,702 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1680C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (4 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.38

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010392129).
• BP6: Variant 2-26464028-C-T is Benign according to our data. Variant chr2-26464028-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178627.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.5039G>A	p.Arg1680His	missense_variant	40/47	ENST00000272371.7
OTOF	NM_194323.3	c.2738G>A	p.Arg913His	missense_variant	23/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.5039G>A	p.Arg1680His	missense_variant	40/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.2738G>A	p.Arg913His	missense_variant	23/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152194 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000854 AC: 214 AN: 250618 Hom.: 1 AF XY: 0.000605 AC XY: 82 AN XY: 135644

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000307 AC: 448 AN: 1461390 Hom.: 4 Cov.: 32 AF XY: 0.000241 AC XY: 175 AN XY: 727004

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.00311 AC: 474 AN: 152312 Hom.: 5 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74476

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000569 Hom.: 2

Bravo AF: 0.00380

ESP6500AA AF: 0.00772 AC: 34

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00119 AC: 144

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	OTOF: BP4, BS1, BS2 -

Autosomal recessive nonsyndromic hearing loss 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

May 07, 2012

Arg1680His in Exon 40 of OTOF: This variant is not expected to have clinical sig nificance because it has been identified in 0.7% (25/3738) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs11893228). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.87	D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.2	N;N;.;N;N;.
REVEL	Benign	0.15
Sift	Benign	0.13	T;T;.;T;T;.
Sift4G	Benign	0.11	T;T;.;T;T;.
Polyphen		0.0020	B;B;.;B;.;B
Vest4		0.12
MVP		0.77
MPC		0.19
ClinPred		0.028	T
GERP RS		2.5
Varity_R		0.042
gMVP		0.46

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: rs11893228; hg19: chr2-26686896;