rs61744348

Variant names:

• chr2-26516422-G-A
• rs61744348
• NM_194248.3:c.505C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26516422-G-A
• chr2-26516422-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_194248.3(OTOF):​c.505C>T​(p.Arg169Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,613,680 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169Q) has been classified as Likely benign. The gene OTOF is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0066 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (14 hom.)
• Consequence: OTOF NM_194248.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.34
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008627802).
• BP6: Variant 2-26516422-G-A is Benign according to our data. Variant chr2-26516422-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48247.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00655 (998/152276) while in subpopulation AFR AF = 0.0218 (904/41534). AF 95% confidence interval is 0.0206. There are 16 homozygotes in GnomAd4. There are 454 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 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.505C>T	p.Arg169Trp	missense	Exon 5 of 47	NP_919224.1	Q9HC10-1
	OTOF	NM_001287489.2		c.505C>T	p.Arg169Trp	missense	Exon 5 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.505C>T	p.Arg169Trp	missense	Exon 5 of 47	ENSP00000272371.2	Q9HC10-1
	OTOF	ENST00000403946.7	TSL:5	c.505C>T	p.Arg169Trp	missense	Exon 5 of 46	ENSP00000385255.3	Q9HC10-5

Frequencies

GnomAD3 genomes AF: 0.00655 AC: 996 AN: 152158 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00193 AC: 485 AN: 250940 AF XY: 0.00150

Gnomad AFR exome AF: 0.0230

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000929 AC: 1357 AN: 1461404 Hom.: 14 Cov.: 33 AF XY: 0.000799 AC XY: 581 AN XY: 726986

African (AFR) AF: 0.0253 AC: 846 AN: 33468

American (AMR) AF: 0.00159 AC: 71 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000613 AC: 16 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5762

European-Non Finnish (NFE) AF: 0.000281 AC: 312 AN: 1111758

Other (OTH) AF: 0.00167 AC: 101 AN: 60376

GnomAD4 genome AF: 0.00655 AC: 998 AN: 152276 Hom.: 16 Cov.: 32 AF XY: 0.00610 AC XY: 454 AN XY: 74454

African (AFR) AF: 0.0218 AC: 904 AN: 41534

American (AMR) AF: 0.00359 AC: 55 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68020

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00115 Hom.: 3

Bravo AF: 0.00736

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00226 AC: 274

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0086	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.67
MVP		0.95
MPC		0.62
ClinPred		0.033	T
GERP RS		5.5
Varity_R		0.36
gMVP		0.42
Mutation Taster		=76/24	polymorphism

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: rs61744348; hg19: chr2-26739290;