rs727505096

chr2-26519086-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP6

The NM_194248.3(OTOF):c.251T>C(p.Val84Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,604,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V84V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 8.66

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746
• BP6: Variant 2-26519086-A-G is Benign according to our data. Variant chr2-26519086-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179742.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.251T>C	p.Val84Ala	missense_variant	4/47	ENST00000272371.7
OTOF	NM_001287489.2	c.251T>C	p.Val84Ala	missense_variant	4/46

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.251T>C	p.Val84Ala	missense_variant	4/47	1	NM_194248.3	A1
OTOF	ENST00000403946.7	c.251T>C	p.Val84Ala	missense_variant	4/46	5		P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000847 AC: 2 AN: 236100 Hom.: 0 AF XY: 0.00000784 AC XY: 1 AN XY: 127600

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1452460 Hom.: 0 Cov.: 31 AF XY: 0.00000416 AC XY: 3 AN XY: 721768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 05, 2014

The Val84Ala variant in OTOF has not been previously reported in individuals wit h hearing loss and was absent from large population studies. Computational predi ction tools and conservation analyses suggest that the Val84Ala variant may impa ct the protein, though this information is not predictive enough to determine pa thogenicity. In summary, the clinical significance of the Val84Ala variant is un certain. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.088	T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.23	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.94	P;.
Vest4		0.79
MutPred		0.44		Gain of ubiquitination at K87 (P = 0.07);Gain of ubiquitination at K87 (P = 0.07);
MVP		0.87
MPC		0.70
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.30
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: rs727505096; hg19: chr2-26741954;