rs138151478

Variant names:

• chr2-26465995-C-T
• rs138151478
• NM_194248.3:c.4582G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-26465995-C-T
• chr2-26465995-C-G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 119/24962) of the c.4582G>A (p.Asp1528Asn) variant in the OTOF gene is 0.407% for African/African-American chromosomes by gnomAD, which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA142894/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Likely benign reviewed by expert panel B:5
• Conservation: PhyloP100: 7.91
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.

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.4582G>A	p.Asp1528Asn	missense	Exon 37 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_194323.3	MANE Plus Clinical	c.2281G>A	p.Asp761Asn	missense	Exon 20 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_001287489.2		c.4582G>A	p.Asp1528Asn	missense	Exon 37 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.4582G>A	p.Asp1528Asn	missense	Exon 37 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2281G>A	p.Asp761Asn	missense	Exon 20 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.2341G>A	p.Asp781Asn	missense	Exon 19 of 29	ENSP00000383906.4	A0A2U3TZT7

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152226 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00547

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000350 AC: 88 AN: 251478 AF XY: 0.000250

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000152 AC: 222 AN: 1461880 Hom.: 1 Cov.: 32 AF XY: 0.000139 AC XY: 101 AN XY: 727244

African (AFR) AF: 0.00556 AC: 186 AN: 33480

American (AMR) AF: 0.000157 AC: 7 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: 0.0000464 AC: 4 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112008

Other (OTH) AF: 0.000281 AC: 17 AN: 60396

GnomAD4 genome AF: 0.00156 AC: 237 AN: 152344 Hom.: 1 Cov.: 33 AF XY: 0.00154 AC XY: 115 AN XY: 74492

African (AFR) AF: 0.00546 AC: 227 AN: 41584

American (AMR) AF: 0.000261 AC: 4 AN: 15308

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

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: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000452 Hom.: 1

Bravo AF: 0.00154

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000371 AC: 45

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Nonsyndromic genetic hearing loss (1)
-	-	1	not specified (1)
-	-	1	OTOF-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.94
MPC		0.52
ClinPred		0.066	T
GERP RS		5.6
Varity_R		0.46
gMVP		0.56
Mutation Taster		=31/69	disease causing

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: rs138151478; hg19: chr2-26688863; COSMIC: COSV55524625;