chr2-26537725-G-A

Variant names:

• chr2-26537725-G-A
• rs116525289
• NM_194248.3:c.129C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_194248.3(OTOF):​c.129C>T​(p.Asp43Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0076 in 1,554,472 control chromosomes in the GnomAD database, including 524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (71 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (453 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.56
• Publications: 4 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-26537725-G-A is Benign according to our data. Variant chr2-26537725-G-A is described in ClinVar as Benign. ClinVar VariationId is 48167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.109 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.129C>T	p.Asp43Asp	synonymous	Exon 2 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_001287489.2		c.129C>T	p.Asp43Asp	synonymous	Exon 2 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.129C>T	p.Asp43Asp	synonymous	Exon 2 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000403946.7	TSL:5	c.129C>T	p.Asp43Asp	synonymous	Exon 2 of 46	ENSP00000385255.3	Q9HC10-5

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2659 AN: 152146 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0137 AC: 2224 AN: 162332 AF XY: 0.0130

Gnomad AFR exome AF: 0.0404

Gnomad AMR exome AF: 0.00423

Gnomad ASJ exome AF: 0.000347

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.00653 AC: 9156 AN: 1402208 Hom.: 453 Cov.: 30 AF XY: 0.00655 AC XY: 4536 AN XY: 692044

African (AFR) AF: 0.0402 AC: 1274 AN: 31702

American (AMR) AF: 0.00486 AC: 177 AN: 36418

Ashkenazi Jewish (ASJ) AF: 0.000277 AC: 7 AN: 25232

East Asian (EAS) AF: 0.143 AC: 5162 AN: 35998

South Asian (SAS) AF: 0.0107 AC: 853 AN: 79408

European-Finnish (FIN) AF: 0.00107 AC: 53 AN: 49462

Middle Eastern (MID) AF: 0.0107 AC: 61 AN: 5696

European-Non Finnish (NFE) AF: 0.000852 AC: 920 AN: 1080198

Other (OTH) AF: 0.0112 AC: 649 AN: 58094

GnomAD4 genome AF: 0.0174 AC: 2652 AN: 152264 Hom.: 71 Cov.: 33 AF XY: 0.0178 AC XY: 1327 AN XY: 74448

African (AFR) AF: 0.0418 AC: 1735 AN: 41544

American (AMR) AF: 0.00843 AC: 129 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.117 AC: 603 AN: 5170

South Asian (SAS) AF: 0.00973 AC: 47 AN: 4830

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68004

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00653 Hom.: 13

Bravo AF: 0.0193

Asia WGS AF: 0.0440 AC: 151 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	-0.49
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		1.6
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: rs116525289; hg19: chr2-26760593; COSMIC: COSV55523655;