rs80214437

Variant names:

• chr2-26467120-C-T
• rs80214437
• NM_194248.3:c.4341G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-26467120-C-T
• chr2-26467120-C-A

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.4341G>A​(p.Glu1447Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00471 in 1,613,820 control chromosomes in the GnomAD database, including 314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (170 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (144 hom.)
• Consequence: OTOF NM_194248.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.802
• 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

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-26467120-C-T is Benign according to our data. Variant chr2-26467120-C-T is described in ClinVar as Benign. ClinVar VariationId is 48234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.802 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0855 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.4341G>A	p.Glu1447Glu	synonymous	Exon 35 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.2040G>A	p.Glu680Glu	synonymous	Exon 18 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.4341G>A	p.Glu1447Glu	synonymous	Exon 35 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.4341G>A	p.Glu1447Glu	synonymous	Exon 35 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2040G>A	p.Glu680Glu	synonymous	Exon 18 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.2100G>A	p.Glu700Glu	synonymous	Exon 17 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3860 AN: 152076 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00656 AC: 1648 AN: 251074 AF XY: 0.00465

Gnomad AFR exome AF: 0.0883

Gnomad AMR exome AF: 0.00471

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00256 AC: 3747 AN: 1461626 Hom.: 144 Cov.: 35 AF XY: 0.00219 AC XY: 1590 AN XY: 727134

African (AFR) AF: 0.0915 AC: 3065 AN: 33480

American (AMR) AF: 0.00550 AC: 246 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53156

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.0000665 AC: 74 AN: 1112008

Other (OTH) AF: 0.00560 AC: 338 AN: 60396

GnomAD4 genome AF: 0.0254 AC: 3859 AN: 152194 Hom.: 170 Cov.: 32 AF XY: 0.0249 AC XY: 1851 AN XY: 74410

African (AFR) AF: 0.0878 AC: 3643 AN: 41472

American (AMR) AF: 0.0112 AC: 172 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68020

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00943 Hom.: 28

Bravo AF: 0.0290

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

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	-0.41
CADD	Benign	6.5
DANN	Benign	0.54
PhyloP100		0.80
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: rs80214437; hg19: chr2-26689988;