rs200670445

chr2-26477188-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_194248.3(OTOF):c.2507G>A(p.Arg836His) variant causes a missense change. The variant allele was found at a frequency of 0.0000553 in 1,610,470 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R836R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.87

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-26477188-C-T is Benign according to our data. Variant chr2-26477188-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178510.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.2507G>A	p.Arg836His	missense_variant	21/47	ENST00000272371.7
OTOF	NM_194323.3	c.266G>A	p.Arg89His	missense_variant	4/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.2507G>A	p.Arg836His	missense_variant	21/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.266G>A	p.Arg89His	missense_variant	4/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000696 AC: 17 AN: 244158 Hom.: 0 AF XY: 0.0000676 AC XY: 9 AN XY: 133162

Gnomad AFR exome AF: 0.000908

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000908

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000295 AC: 43 AN: 1458288 Hom.: 0 Cov.: 33 AF XY: 0.0000290 AC XY: 21 AN XY: 725318

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74352

Gnomad4 AFR AF: 0.000941

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000209 Hom.: 1

Bravo AF: 0.000306

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000116 AC: 14

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 27, 2014

The p.Arg836His variant in OTOF has not been previously reported in individuals with hearing loss, but has been identified in 0.01% (1/8583) of European America n chromosomes and 0.02% (1/4367) of African American chromosomes by the NHLBI Ex ome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs200670445). A lthough this variant has been seen in the general population, its frequency is n ot high enough to rule out a pathogenic role. The Arginine (Arg) at position 836 is highly conserved in mammals and evolutionary distant species, raising the po ssibility that a change at this position may not be tolerated. However, addition al computational prediction tools do not provide strong support for or against a n impact to the protein. In summary, the clinical significance of the p.Arg836Hi s variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.9	D;D;.;D;D;.
REVEL	Pathogenic	0.81
Sift	Benign	0.069	T;T;.;T;T;.
Sift4G	Benign	0.064	T;T;.;T;T;.
Polyphen		0.92	P;D;.;D;.;D
Vest4		0.84
MVP		0.94
MPC		0.56
ClinPred		0.26	T
GERP RS		5.0
Varity_R		0.65
gMVP		0.59

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: rs200670445; hg19: chr2-26700056;