rs201326023

chr2-26458218-C-Achr2-26458218-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_194323.3(OTOF):c.3515G>T(p.Arg1172Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,070 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1172Q) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: OTOF NM_194323.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.83

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain C2 5 (size 127) in uniprot entity OTOF_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_194323.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-26458218-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 548986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTOF	NM_194323.3	c.3515G>T	p.Arg1172Leu	missense_variant, splice_region_variant	29/29	ENST00000339598.8
OTOF	NM_194248.3	c.*20G>T		splice_region_variant, 3_prime_UTR_variant	47/47	ENST00000272371.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTOF	ENST00000339598.8	c.3515G>T	p.Arg1172Leu	missense_variant, splice_region_variant	29/29	1	NM_194323.3
OTOF	ENST00000272371.7	c.*20G>T		splice_region_variant, 3_prime_UTR_variant	47/47	1	NM_194248.3	A1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152070 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152070 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74272

Gnomad4 AFR AF: 0.0000483

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Benign	17
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.70	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.67		Loss of disorder (P = 0.0632);.;
MVP		0.96
ClinPred		0.98	D
GERP RS		4.8

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: rs201326023; hg19: chr2-26681086;