NM_001378609.3:c.1395-12A>G

Variant names:

• chr12-80254512-A-G
• rs138572593
• NM_001378609.3:c.1395-12A>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_001378609.3(OTOGL):​c.1395-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,595,856 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: OTOGL NM_001378609.3 intron
• Scores: Splicing: ADA: 0.0003948
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0440
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 12-80254512-A-G is Benign according to our data. Variant chr12-80254512-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 504792.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 = 0.00168 (256/152020) while in subpopulation AFR AF = 0.00602 (250/41494). AF 95% confidence interval is 0.00541. There are 2 homozygotes in GnomAd4. There are 126 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1395-12A>G		intron	N/A	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.1395-12A>G		intron	N/A	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.1395-12A>G		intron	N/A	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.1395-12A>G		intron	N/A	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.1395-12A>G		intron	N/A	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000643417.1		n.2055-12A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 253 AN: 151902 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00597

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000402 AC: 98 AN: 243550 AF XY: 0.000287

Gnomad AFR exome AF: 0.00583

Gnomad AMR exome AF: 0.000264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000173 AC: 250 AN: 1443836 Hom.: 0 Cov.: 29 AF XY: 0.000155 AC XY: 111 AN XY: 718282

African (AFR) AF: 0.00640 AC: 212 AN: 33132

American (AMR) AF: 0.000406 AC: 18 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25798

East Asian (EAS) AF: 0.00 AC: 0 AN: 39468

South Asian (SAS) AF: 0.00 AC: 0 AN: 83446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52628

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5720

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099704

Other (OTH) AF: 0.000319 AC: 19 AN: 59596

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152020 Hom.: 2 Cov.: 32 AF XY: 0.00170 AC XY: 126 AN XY: 74330

African (AFR) AF: 0.00602 AC: 250 AN: 41494

American (AMR) AF: 0.000393 AC: 6 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67900

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000854 Hom.: 1

Bravo AF: 0.00205

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	-0.73
CADD	Benign	0.85
DANN	Benign	0.77
PhyloP100		0.044
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.028
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: rs138572593; hg19: chr12-80648292;