rs72853726

Variant names:

• chr2-26465851-G-A
• rs72853726
• NM_194248.3:c.4629-9C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26465851-G-A
• chr2-26465851-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_194248.3(OTOF):​c.4629-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,614,234 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (42 hom.)
• Consequence: OTOF NM_194248.3 intron
• Scores: Splicing: ADA: 0.00001618
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.33
• Publications: 1 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 Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-26465851-G-A is Benign according to our data. Variant chr2-26465851-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 48239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0117 (1790/152360) while in subpopulation AFR AF = 0.0373 (1552/41578). AF 95% confidence interval is 0.0358. There are 26 homozygotes in GnomAd4. There are 855 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR 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.4629-9C>T		intron	N/A	NP_919224.1
	OTOF	NM_194323.3	MANE Plus Clinical	c.2328-9C>T		intron	N/A	NP_919304.1
	OTOF	NM_001287489.2		c.4629-9C>T		intron	N/A	NP_001274418.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000272371.7	TSL:1 MANE Select	c.4629-9C>T		intron	N/A	ENSP00000272371.2
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.2328-9C>T		intron	N/A	ENSP00000344521.3
	OTOF	ENST00000402415.8	TSL:1	c.2388-9C>T		intron	N/A	ENSP00000383906.4

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1776 AN: 152242 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00456 AC: 1146 AN: 251350 AF XY: 0.00394

Gnomad AFR exome AF: 0.0394

Gnomad AMR exome AF: 0.00567

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00243 AC: 3551 AN: 1461874 Hom.: 42 Cov.: 32 AF XY: 0.00237 AC XY: 1721 AN XY: 727232

African (AFR) AF: 0.0412 AC: 1378 AN: 33480

American (AMR) AF: 0.00590 AC: 264 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26134

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

South Asian (SAS) AF: 0.00274 AC: 236 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.0121 AC: 70 AN: 5768

European-Non Finnish (NFE) AF: 0.00114 AC: 1270 AN: 1112000

Other (OTH) AF: 0.00530 AC: 320 AN: 60396

GnomAD4 genome AF: 0.0117 AC: 1790 AN: 152360 Hom.: 26 Cov.: 33 AF XY: 0.0115 AC XY: 855 AN XY: 74494

African (AFR) AF: 0.0373 AC: 1552 AN: 41578

American (AMR) AF: 0.00719 AC: 110 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68040

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

Alfa AF: 0.00834 Hom.: 20

Bravo AF: 0.0137

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.24
DANN	Benign	0.50
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
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: rs72853726; hg19: chr2-26688719;