rs117005078

Variant names:

• chr11-17599671-C-A
• NM_001292063.2:c.3683C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-17599671-C-A
• chr11-17599671-C-G
• chr11-17599671-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001292063.2(OTOG):​c.3683C>A​(p.Pro1228Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000286 in 1,398,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: OTOG NM_001292063.2 missense, splice_region
• Scores: Splicing: ADA: 0.9458
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.05

Genes affected

OTOG (HGNC:8516): (otogelin) The protein encoded by this gene is a component of the acellular membranes of the inner ear. Disruption of the orthologous mouse gene shows that it plays a role in auditory and vestibular functions. It is involved in fibrillar network organization, the anchoring of otoconial membranes and cupulae to the neuroepithelia, and likely in sound stimulation resistance. Mutations in this gene cause autosomal recessive nonsyndromic deafness, type 18B. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTOG	NM_001292063.2	c.3683C>A	p.Pro1228Gln	missense_variant, splice_region_variant	Exon 31 of 56	ENST00000399397.6	NP_001278992.1
OTOG	NM_001277269.2	c.3719C>A	p.Pro1240Gln	missense_variant, splice_region_variant	Exon 30 of 55		NP_001264198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTOG	ENST00000399397.6	c.3683C>A	p.Pro1228Gln	missense_variant, splice_region_variant	Exon 31 of 56	5	NM_001292063.2	ENSP00000382329.2
OTOG	ENST00000399391.7	c.3719C>A	p.Pro1240Gln	missense_variant, splice_region_variant	Exon 30 of 55	5		ENSP00000382323.2
OTOG	ENST00000342528.2	n.1048-2539C>A		intron_variant	Intron 7 of 21	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1398358 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689700

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000371

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T;T
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.8	H;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.2	D;.
REVEL	Pathogenic	0.79
Sift	Benign	0.045	D;.
Sift4G	Uncertain	0.0020	D;D
Vest4		0.81
MutPred		0.80		Gain of relative solvent accessibility (P = 0.1259);.;
MVP		0.59
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.22
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.76
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-17621218;