2-26477904-T-C

Variant names:

• chr2-26477904-T-C
• rs143933877
• NM_194323.3:c.-88A>G

Variant summary

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

The NM_194323.3(OTOF):​c.-88A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000971 in 1,534,770 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00077 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (22 hom.)
• Consequence: OTOF NM_194323.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.137
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 2-26477904-T-C is Benign according to our data. Variant chr2-26477904-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 179695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000769 (117/152098) while in subpopulation SAS AF = 0.0112 (54/4820). AF 95% confidence interval is 0.00882. There are 3 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194323.3. 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_194323.3	MANE Plus Clinical	c.-88A>G		5_prime_UTR	Exon 1 of 29	NP_919304.1	Q9HC10-2
	OTOF	NM_194248.3	MANE Select	c.2215-155A>G		intron	N/A	NP_919224.1	Q9HC10-1
	OTOF	NM_194322.3		c.-11A>G		5_prime_UTR	Exon 1 of 29	NP_919303.1	Q9HC10-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOF	ENST00000339598.8	TSL:1 MANE Plus Clinical	c.-88A>G		5_prime_UTR	Exon 1 of 29	ENSP00000344521.3	Q9HC10-2
	OTOF	ENST00000402415.8	TSL:1	c.-182A>G		5_prime_UTR	Exon 1 of 29	ENSP00000383906.4	A0A2U3TZT7
	OTOF	ENST00000338581.10	TSL:1	c.-88A>G		5_prime_UTR	Exon 1 of 30	ENSP00000345137.6	Q9HC10-4

Frequencies

GnomAD3 genomes AF: 0.000776 AC: 118 AN: 151980 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00206 AC: 299 AN: 145334 AF XY: 0.00263

Gnomad AFR exome AF: 0.000383

Gnomad AMR exome AF: 0.000527

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000450

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.000994 AC: 1374 AN: 1382672 Hom.: 22 Cov.: 35 AF XY: 0.00133 AC XY: 908 AN XY: 680176

African (AFR) AF: 0.000420 AC: 13 AN: 30936

American (AMR) AF: 0.000650 AC: 22 AN: 33854

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 30 AN: 24296

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35534

South Asian (SAS) AF: 0.0115 AC: 889 AN: 77518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47498

Middle Eastern (MID) AF: 0.0102 AC: 57 AN: 5586

European-Non Finnish (NFE) AF: 0.000257 AC: 275 AN: 1070222

Other (OTH) AF: 0.00152 AC: 87 AN: 57228

GnomAD4 genome AF: 0.000769 AC: 117 AN: 152098 Hom.: 3 Cov.: 32 AF XY: 0.000996 AC XY: 74 AN XY: 74330

African (AFR) AF: 0.000169 AC: 7 AN: 41472

American (AMR) AF: 0.000916 AC: 14 AN: 15284

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5150

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 68000

Other (OTH) AF: 0.00190 AC: 4 AN: 2104

Alfa AF: 0.000755 Hom.: 0

Bravo AF: 0.000487

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	6.0
DANN	Benign	0.50
PhyloP100		0.14
PromoterAI		0.018	Neutral
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143933877; hg19: chr2-26700772;