rs61744000

Variant names:

• chr2-26464960-G-A
• rs61744000
• NM_194248.3:c.4869C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_194248.3(OTOF):​c.4869C>T​(p.Gly1623Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000773 in 1,563,330 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (3 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.55
• Publications: 2 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

Specifications for OTOF are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 2-26464960-G-A is Benign according to our data. Variant chr2-26464960-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48242.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0041 (625/152268) while in subpopulation AFR AF = 0.0133 (554/41556). AF 95% confidence interval is 0.0124. There are 3 homozygotes in GnomAd4. There are 297 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	NM_194248.3	MANE Select	c.4869C>T	p.Gly1623Gly	synonymous	Exon 39 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.2568C>T	p.Gly856Gly	synonymous	Exon 22 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.4869C>T	p.Gly1623Gly	synonymous	Exon 39 of 46	NP_001274418.1	Q9HC10-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.4869C>T	p.Gly1623Gly	synonymous	Exon 39 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2568C>T	p.Gly856Gly	synonymous	Exon 22 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.2628C>T	p.Gly876Gly	synonymous	Exon 21 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 624 AN: 152150 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00114 AC: 248 AN: 217890 AF XY: 0.000783

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000693

Gnomad OTH exome AF: 0.000395

GnomAD4 exome AF: 0.000414 AC: 584 AN: 1411062 Hom.: 3 Cov.: 31 AF XY: 0.000364 AC XY: 254 AN XY: 698030

African (AFR) AF: 0.0127 AC: 390 AN: 30796

American (AMR) AF: 0.00166 AC: 66 AN: 39692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23936

East Asian (EAS) AF: 0.00 AC: 0 AN: 38194

South Asian (SAS) AF: 0.0000257 AC: 2 AN: 77898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52280

Middle Eastern (MID) AF: 0.000360 AC: 2 AN: 5558

European-Non Finnish (NFE) AF: 0.0000489 AC: 53 AN: 1084562

Other (OTH) AF: 0.00122 AC: 71 AN: 58146

GnomAD4 genome AF: 0.00410 AC: 625 AN: 152268 Hom.: 3 Cov.: 33 AF XY: 0.00399 AC XY: 297 AN XY: 74458

African (AFR) AF: 0.0133 AC: 554 AN: 41556

American (AMR) AF: 0.00366 AC: 56 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68008

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00272 Hom.: 1

Bravo AF: 0.00461

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	-	Autosomal recessive nonsyndromic hearing loss 9 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.65
PhyloP100		1.6
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: 2

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

Other links and lift over

dbSNP: rs61744000; hg19: chr2-26687828;