rs73920285

Variant names:

• chr2-26476165-G-A
• rs73920285
• NM_194248.3:c.2829C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26476165-G-A
• chr2-26476165-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):​c.2829C>T​(p.Gly943Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00709 in 1,611,102 control chromosomes in the GnomAD database, including 629 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.037 (326 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (303 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.306
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-26476165-G-A is Benign according to our data. Variant chr2-26476165-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.306 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

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.2829C>T	p.Gly943Gly	synonymous	Exon 23 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.588C>T	p.Gly196Gly	synonymous	Exon 6 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.2829C>T	p.Gly943Gly	synonymous	Exon 23 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.2829C>T	p.Gly943Gly	synonymous	Exon 23 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.588C>T	p.Gly196Gly	synonymous	Exon 6 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.588C>T	p.Gly196Gly	synonymous	Exon 5 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5565 AN: 152044 Hom.: 327 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.00967 AC: 2387 AN: 246862 AF XY: 0.00709

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.00604

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000486

Gnomad NFE exome AF: 0.000684

Gnomad OTH exome AF: 0.00496

GnomAD4 exome AF: 0.00401 AC: 5850 AN: 1458940 Hom.: 303 Cov.: 33 AF XY: 0.00343 AC XY: 2493 AN XY: 725780

African (AFR) AF: 0.129 AC: 4334 AN: 33470

American (AMR) AF: 0.00689 AC: 308 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86216

European-Finnish (FIN) AF: 0.0000392 AC: 2 AN: 51074

Middle Eastern (MID) AF: 0.00904 AC: 52 AN: 5754

European-Non Finnish (NFE) AF: 0.000560 AC: 622 AN: 1111646

Other (OTH) AF: 0.00856 AC: 516 AN: 60310

GnomAD4 genome AF: 0.0366 AC: 5574 AN: 152162 Hom.: 326 Cov.: 32 AF XY: 0.0356 AC XY: 2646 AN XY: 74412

African (AFR) AF: 0.126 AC: 5232 AN: 41462

American (AMR) AF: 0.0158 AC: 242 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 67976

Other (OTH) AF: 0.0260 AC: 55 AN: 2112

Alfa AF: 0.0131 Hom.: 39

Bravo AF: 0.0416

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000712

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	2.9
DANN	Benign	0.61
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs73920285; hg19: chr2-26699033;