rs147195954

Variant names:

• chr12-80238893-C-T
• rs147195954
• NM_001378609.3:c.860C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001378609.3(OTOGL):​c.860C>T​(p.Ser287Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,579,910 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S287S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0770
• Publications: 6 publications found

Genes affected

OTOGL (HGNC:26901): (otogelin like) The protein encoded by this gene belongs to the otogelin family. This gene is expressed in the inner ear of vertebrates with the highest level of expression seen at the embryonic stage and lowest in adult. Knockdown studies in zebrafish suggest that this gene is essential for normal inner ear function. Mutations in this gene are associated with autosomal recessive deafness. [provided by RefSeq, Dec 2012]

OTOGL Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 84B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009349346).
• BP6: Variant 12-80238893-C-T is Benign according to our data. Variant chr12-80238893-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504844.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378609.3. 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
	OTOGL	NM_001378609.3	MANE Select	c.860C>T	p.Ser287Leu	missense	Exon 10 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.860C>T	p.Ser287Leu	missense	Exon 13 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.860C>T	p.Ser287Leu	missense	Exon 10 of 59	NP_775862.4	Q3ZCN5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOGL	ENST00000547103.7	TSL:5 MANE Select	c.860C>T	p.Ser287Leu	missense	Exon 10 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.860C>T	p.Ser287Leu	missense	Exon 15 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000643417.1		n.1520C>T		non_coding_transcript_exon	Exon 13 of 23

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 151856 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000789

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000843 AC: 175 AN: 207580 AF XY: 0.000783

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000664

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.000917

GnomAD4 exome AF: 0.00136 AC: 1937 AN: 1427938 Hom.: 3 Cov.: 32 AF XY: 0.00128 AC XY: 910 AN XY: 708560

African (AFR) AF: 0.000301 AC: 10 AN: 33172

American (AMR) AF: 0.000710 AC: 30 AN: 42272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25762

East Asian (EAS) AF: 0.00 AC: 0 AN: 39070

South Asian (SAS) AF: 0.000410 AC: 34 AN: 82990

European-Finnish (FIN) AF: 0.00121 AC: 46 AN: 38086

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5746

European-Non Finnish (NFE) AF: 0.00158 AC: 1744 AN: 1101272

Other (OTH) AF: 0.00119 AC: 71 AN: 59568

GnomAD4 genome AF: 0.00112 AC: 170 AN: 151972 Hom.: 1 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74264

African (AFR) AF: 0.000482 AC: 20 AN: 41472

American (AMR) AF: 0.000788 AC: 12 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000832 AC: 4 AN: 4810

European-Finnish (FIN) AF: 0.00180 AC: 19 AN: 10556

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

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 67968

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00140 Hom.: 0

Bravo AF: 0.000929

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.00132 AC: 11

ExAC AF: 0.000714 AC: 85

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.2
DANN	Benign	0.73
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.077
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.060
Sift	Benign	0.37	T
Sift4G	Benign	0.42	T
Vest4		0.096
MVP		0.040
MPC		0.021
ClinPred		0.0098	T
GERP RS		-8.4
gMVP		0.43
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs147195954; hg19: chr12-80632673; COSMIC: COSV72005624;