rs774929350

chr2-26470698-C-Achr2-26470698-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_194248.3(OTOF):c.3918G>T(p.Lys1306Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1306T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24755567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194248.3	c.3918G>T	p.Lys1306Asn	missense_variant	32/47	ENST00000272371.7
OTOF	NM_194323.3	c.1617G>T	p.Lys539Asn	missense_variant	15/29	ENST00000339598.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000272371.7	c.3918G>T	p.Lys1306Asn	missense_variant	32/47	1	NM_194248.3	A1
OTOF	ENST00000339598.8	c.1617G>T	p.Lys539Asn	missense_variant	15/29	1	NM_194323.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	0.066
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T;T;T;T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N;N;.;N;N;.
REVEL	Benign	0.23
Sift	Benign	0.37	T;T;.;T;T;.
Sift4G	Benign	0.085	T;T;.;T;T;.
Polyphen		0.28	B;B;.;B;.;B
Vest4		0.52
MutPred		0.28		.;.;.;Loss of methylation at K1306 (P = 0.0097);Loss of methylation at K1306 (P = 0.0097);.;
MVP		0.88
MPC		0.18
ClinPred		0.77	D
GERP RS		5.5
Varity_R		0.17
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs774929350; hg19: chr2-26693566;