2-26477904-T-G

Variant names:

• chr2-26477904-T-G
• rs143933877
• NM_194323.3:c.-88A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_194323.3(OTOF):​c.-88A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000362 in 1,382,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: OTOF NM_194323.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.137
• Publications: 0 publications found

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]

OTOF Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 9

  Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194323.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194323.3	MANE Plus Clinical	c.-88A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_194323.3	MANE Plus Clinical	c.-88A>C		5_prime_UTR	Exon 1 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_194248.3	MANE Select	c.2215-155A>C		intron	N/A	NP_919224.1	Q9HC10-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.-88A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.-182A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 29	ENSP00000383906.4	A0A2U3TZT7
	OTOF	ENST00000338581.10	TSL:1	c.-88A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 30	ENSP00000345137.6	Q9HC10-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000688 AC: 1 AN: 145334 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000362 AC: 5 AN: 1382674 Hom.: 0 Cov.: 35 AF XY: 0.00000147 AC XY: 1 AN XY: 680176

African (AFR) AF: 0.00 AC: 0 AN: 30936

American (AMR) AF: 0.00 AC: 0 AN: 33854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24296

East Asian (EAS) AF: 0.00 AC: 0 AN: 35534

South Asian (SAS) AF: 0.00 AC: 0 AN: 77520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00000467 AC: 5 AN: 1070222

Other (OTH) AF: 0.00 AC: 0 AN: 57228

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.6
DANN	Benign	0.49
PhyloP100		0.14
PromoterAI		0.067	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143933877; hg19: chr2-26700772;