2-26461838-G-C

Position:

• chr2-26461838-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_194248.3(OTOF):​c.5391C>G​(p.Phe1797Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F1797F) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0640

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 5 ACMG points.

• PM1: In a domain C2 7 (size 151) in uniprot entity OTOF_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_194248.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.5391C>G	p.Phe1797Leu	missense_variant	43/47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.3090C>G	p.Phe1030Leu	missense_variant	26/29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.5391C>G	p.Phe1797Leu	missense_variant	43/47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.3090C>G	p.Phe1030Leu	missense_variant	26/29	1	NM_194323.3	ENSP00000344521.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	.;.;.;D;.;.
Eigen	Benign	0.10
Eigen_PC	Benign	0.037
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.91	D;D;T;T;D;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.3	.;.;.;M;M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.9	D;D;.;D;D;.
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;.;D;D;.
Sift4G	Uncertain	0.010	D;D;.;D;D;.
Polyphen		0.80	P;P;.;P;.;P
Vest4		0.91
MutPred		0.44		.;.;.;Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);.;
MVP		0.91
MPC		0.41
ClinPred		0.99	D
GERP RS		2.2
Varity_R		0.87
gMVP		0.83

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: rs61747275; hg19: chr2-26684706;