NM_194248.3:c.4799+16G>A

Variant names:

• chr2-26465656-C-T
• rs60083916
• NM_194248.3:c.4799+16G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_194248.3(OTOF):​c.4799+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,613,758 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (44 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (52 hom.)
• Consequence: OTOF NM_194248.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.21
• Publications: 1 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 Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-26465656-C-T is Benign according to our data. Variant chr2-26465656-C-T is described in ClinVar as Benign. ClinVar VariationId is 263084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0148 (2253/152372) while in subpopulation AFR AF = 0.0477 (1985/41586). AF 95% confidence interval is 0.046. There are 44 homozygotes in GnomAd4. There are 1072 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194248.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.4799+16G>A		intron	N/A	NP_919224.1
	OTOF	NM_194323.3	MANE Plus Clinical	c.2498+16G>A		intron	N/A	NP_919304.1
	OTOF	NM_001287489.2		c.4799+16G>A		intron	N/A	NP_001274418.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.4799+16G>A		intron	N/A	ENSP00000272371.2
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2498+16G>A		intron	N/A	ENSP00000344521.3
	OTOF	ENST00000402415.8	TSL:1	c.2558+16G>A		intron	N/A	ENSP00000383906.4

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2238 AN: 152254 Hom.: 43 Cov.: 33

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00863

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00145

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00515 AC: 1295 AN: 251306 AF XY: 0.00428

Gnomad AFR exome AF: 0.0506

Gnomad AMR exome AF: 0.00616

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00187

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00271 AC: 3961 AN: 1461386 Hom.: 52 Cov.: 32 AF XY: 0.00255 AC XY: 1854 AN XY: 727050

African (AFR) AF: 0.0518 AC: 1734 AN: 33472

American (AMR) AF: 0.00655 AC: 293 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5764

European-Non Finnish (NFE) AF: 0.00132 AC: 1472 AN: 1111570

Other (OTH) AF: 0.00583 AC: 352 AN: 60382

GnomAD4 genome AF: 0.0148 AC: 2253 AN: 152372 Hom.: 44 Cov.: 33 AF XY: 0.0144 AC XY: 1072 AN XY: 74504

African (AFR) AF: 0.0477 AC: 1985 AN: 41586

American (AMR) AF: 0.00862 AC: 132 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68044

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00833 Hom.: 6

Bravo AF: 0.0169

Asia WGS AF: 0.00722 AC: 26 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.34
DANN	Benign	0.76
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs60083916; hg19: chr2-26688524;