rs7592040

Variant names:

• chr2-26518683-G-A
• rs7592040
• NM_194248.3:c.327+327C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-26518683-G-A
• chr2-26518683-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_194248.3(OTOF):​c.327+327C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 152,232 control chromosomes in the GnomAD database, including 6,029 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (6029 hom., cov: 35)
• Consequence: OTOF NM_194248.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.875
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOF	NM_194248.3	c.327+327C>T		intron_variant	Intron 4 of 46	ENST00000272371.7	NP_919224.1
OTOF	NM_001287489.2	c.327+327C>T		intron_variant	Intron 4 of 45		NP_001274418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOF	ENST00000272371.7	c.327+327C>T		intron_variant	Intron 4 of 46	1	NM_194248.3	ENSP00000272371.2
OTOF	ENST00000403946.7	c.327+327C>T		intron_variant	Intron 4 of 45	5		ENSP00000385255.3

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38756 AN: 152114 Hom.: 6021 Cov.: 35

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.221

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.255 AC: 38772 AN: 152232 Hom.: 6029 Cov.: 35 AF XY: 0.265 AC XY: 19723 AN XY: 74430

African (AFR) AF: 0.116 AC: 4811 AN: 41564

American (AMR) AF: 0.244 AC: 3733 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 904 AN: 3472

East Asian (EAS) AF: 0.562 AC: 2907 AN: 5170

South Asian (SAS) AF: 0.348 AC: 1680 AN: 4826

European-Finnish (FIN) AF: 0.480 AC: 5088 AN: 10594

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18816 AN: 67986

Other (OTH) AF: 0.228 AC: 482 AN: 2114

Alfa AF: 0.267 Hom.: 21987

Bravo AF: 0.233

Asia WGS AF: 0.468 AC: 1628 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.4
DANN	Benign	0.69
PhyloP100		0.88
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: rs7592040; hg19: chr2-26741551;