rs774929350

Variant names:

• chr2-26470698-C-A
• rs774929350
• NM_194248.3:c.3918G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26470698-C-A
• chr2-26470698-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.

• 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 rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.3918G>T	p.Lys1306Asn	missense_variant	Exon 32 of 47	ENST00000272371.7	NP_919224.1
OTOF	NM_194323.3	c.1617G>T	p.Lys539Asn	missense_variant	Exon 15 of 29	ENST00000339598.8	NP_919304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.3918G>T	p.Lys1306Asn	missense_variant	Exon 32 of 47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000339598.8	c.1617G>T	p.Lys539Asn	missense_variant	Exon 15 of 29	1	NM_194323.3	ENSP00000344521.3

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
DEOGEN2	Benign	0.17	.;.;.;T;.;.
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
MutationAssessor	Benign	1.8	.;.;.;L;L;.
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;