chr2-26516481-G-T

Position:

• chr2-26516481-G-T

Variant summary

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

The NM_194248.3(OTOF):​c.446C>A​(p.Thr149Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.39

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOF	NM_194248.3	c.446C>A	p.Thr149Lys	missense_variant	5/47	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.446C>A	p.Thr149Lys	missense_variant	5/46		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.446C>A	p.Thr149Lys	missense_variant	5/47	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.446C>A	p.Thr149Lys	missense_variant	5/46	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461618 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.83	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.80	P;.
Vest4		0.64
MutPred		0.26		Gain of ubiquitination at T149 (P = 9e-04);Gain of ubiquitination at T149 (P = 9e-04);
MVP		0.93
MPC		0.72
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.22
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: rs140454738; hg19: chr2-26739349;