rs35397172

Variant names:

• chr12-80358753-A-G
• rs35397172
• NM_001378609.3:c.6204A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001378609.3(OTOGL):​c.6204A>G​(p.Gln2068Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000716 in 1,610,840 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (8 hom.)
• Consequence: OTOGL NM_001378609.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0650
• Publications: 0 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 12-80358753-A-G is Benign according to our data. Variant chr12-80358753-A-G is described in ClinVar as Benign. ClinVar VariationId is 226965.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 = 0.00356 (543/152320) while in subpopulation AFR AF = 0.0125 (518/41574). AF 95% confidence interval is 0.0116. There are 9 homozygotes in GnomAd4. There are 278 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.6204A>G	p.Gln2068Gln	synonymous	Exon 51 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.6204A>G	p.Gln2068Gln	synonymous	Exon 54 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.6204A>G	p.Gln2068Gln	synonymous	Exon 51 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.6204A>G	p.Gln2068Gln	synonymous	Exon 51 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.6069A>G	p.Gln2023Gln	synonymous	Exon 55 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.1503A>G	p.Gln501Gln	synonymous	Exon 12 of 18	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 539 AN: 152202 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000893 AC: 221 AN: 247586 AF XY: 0.000754

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000697

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000419 AC: 611 AN: 1458520 Hom.: 8 Cov.: 32 AF XY: 0.000360 AC XY: 261 AN XY: 725748

African (AFR) AF: 0.0140 AC: 469 AN: 33404

American (AMR) AF: 0.000985 AC: 44 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53148

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1109382

Other (OTH) AF: 0.00103 AC: 62 AN: 60270

GnomAD4 genome AF: 0.00356 AC: 543 AN: 152320 Hom.: 9 Cov.: 32 AF XY: 0.00373 AC XY: 278 AN XY: 74484

African (AFR) AF: 0.0125 AC: 518 AN: 41574

American (AMR) AF: 0.00150 AC: 23 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

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

Alfa AF: 0.00108 Hom.: 1

Bravo AF: 0.00414

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.58
PhyloP100		-0.065
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35397172; hg19: chr12-80752533;