rs17005371

chr2-26464893-G-Achr2-26464893-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_194248.3(OTOF):c.4936C>T(p.Pro1646Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0343 in 1,600,522 control chromosomes in the GnomAD database, including 8,235 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. P1646T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.14 (4306 hom., cov: 32)
  • Exomes 𝑓: 0.023 (3929 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 6.62

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=0.0014489889).
• BP6: Variant 2-26464893-G-A is Benign according to our data. Variant chr2-26464893-G-A is described in ClinVar as [Benign]. Clinvar id is 21856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-26464893-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.4936C>T	p.Pro1646Ser	missense_variant	39/47	ENST00000272371.7
OTOF	NM_194323.3	c.2635C>T	p.Pro879Ser	missense_variant	22/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.4936C>T	p.Pro1646Ser	missense_variant	39/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.2635C>T	p.Pro879Ser	missense_variant	22/29	1	NM_194323.3

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20919 AN: 151994 Hom.: 4284 Cov.: 32

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0682

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.0437 AC: 10621 AN: 243164 Hom.: 1661 AF XY: 0.0363 AC XY: 4778 AN XY: 131564

Gnomad AFR exome AF: 0.449

Gnomad AMR exome AF: 0.0286

Gnomad ASJ exome AF: 0.0457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0313

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0357

GnomAD4 exome AF: 0.0234 AC: 33854 AN: 1448410 Hom.: 3929 Cov.: 31 AF XY: 0.0225 AC XY: 16163 AN XY: 719826

Gnomad4 AFR exome AF: 0.463

Gnomad4 AMR exome AF: 0.0338

Gnomad4 ASJ exome AF: 0.0484

Gnomad4 EAS exome AF: 0.0000511

Gnomad4 SAS exome AF: 0.0319

Gnomad4 FIN exome AF: 0.000488

Gnomad4 NFE exome AF: 0.00935

Gnomad4 OTH exome AF: 0.0443

GnomAD4 genome AF: 0.138 AC: 20988 AN: 152112 Hom.: 4306 Cov.: 32 AF XY: 0.134 AC XY: 9959 AN XY: 74360

Gnomad4 AFR AF: 0.450

Gnomad4 AMR AF: 0.0681

Gnomad4 ASJ AF: 0.0404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0235 Hom.: 596

Bravo AF: 0.159

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.442 AC: 1949

ESP6500EA AF: 0.0128 AC: 110

ExAC AF: 0.0544 AC: 6601

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	GeneDx	Nov 10, 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	Eurofins Ntd Llc (ga)	Mar 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -

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

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.00076
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
MetaRNN	Benign	0.0014	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.0000014	P;P;P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.5	N;N;.;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.17	T;T;.;T;T;.
Sift4G	Benign	0.25	T;T;.;T;T;.
Polyphen		0.010	B;B;.;B;.;B
Vest4		0.40
MPC		0.29
ClinPred		0.021	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.53

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: rs17005371; hg19: chr2-26687761; COSMIC: COSV55510289;