rs7312569

Variant names:

• chr12-80353429-C-G
• rs7312569
• NM_001378609.3:c.5512C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-80353429-C-G
• chr12-80353429-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001378609.3(OTOGL):​c.5512C>G​(p.Leu1838Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,600,620 control chromosomes in the GnomAD database, including 30,377 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2751 hom., cov: 33)
  • Exomes 𝑓: 0.19 (27626 hom.)
• Consequence: OTOGL NM_001378609.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.325
• Publications: 15 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 -16 ACMG points.

• BP6: Variant 12-80353429-C-G is Benign according to our data. Variant chr12-80353429-C-G is described in ClinVar as Benign. ClinVar VariationId is 226956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

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.5512C>G	p.Leu1838Val	missense	Exon 46 of 59	NP_001365538.2	Q3ZCN5
	OTOGL	NM_001378610.3		c.5512C>G	p.Leu1838Val	missense	Exon 49 of 62	NP_001365539.2	Q3ZCN5
	OTOGL	NM_173591.7		c.5512C>G	p.Leu1838Val	missense	Exon 46 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.5512C>G	p.Leu1838Val	missense	Exon 46 of 59	ENSP00000447211.2	Q3ZCN5
	OTOGL	ENST00000646859.1		c.5377C>G	p.Leu1793Val	missense	Exon 50 of 63	ENSP00000496036.1	A0A2R8YF04
	OTOGL	ENST00000298820.7	TSL:5	c.811C>G	p.Leu271Val	missense	Exon 7 of 18	ENSP00000298820.3	H7BXL6

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28086 AN: 152054 Hom.: 2750 Cov.: 33

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.0512

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.176 AC: 40545 AN: 229808 AF XY: 0.179

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.185

Gnomad EAS exome AF: 0.0441

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.189

GnomAD4 exome AF: 0.191 AC: 276908 AN: 1448448 Hom.: 27626 Cov.: 30 AF XY: 0.192 AC XY: 138055 AN XY: 719156

African (AFR) AF: 0.176 AC: 5872 AN: 33276

American (AMR) AF: 0.205 AC: 8803 AN: 42968

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4822 AN: 25846

East Asian (EAS) AF: 0.0385 AC: 1516 AN: 39390

South Asian (SAS) AF: 0.208 AC: 17415 AN: 83550

European-Finnish (FIN) AF: 0.110 AC: 5820 AN: 52912

Middle Eastern (MID) AF: 0.218 AC: 1250 AN: 5742

European-Non Finnish (NFE) AF: 0.199 AC: 220227 AN: 1104820

Other (OTH) AF: 0.187 AC: 11183 AN: 59944

GnomAD4 genome AF: 0.185 AC: 28088 AN: 152172 Hom.: 2751 Cov.: 33 AF XY: 0.182 AC XY: 13508 AN XY: 74410

African (AFR) AF: 0.181 AC: 7511 AN: 41526

American (AMR) AF: 0.215 AC: 3283 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 637 AN: 3470

East Asian (EAS) AF: 0.0513 AC: 265 AN: 5164

South Asian (SAS) AF: 0.217 AC: 1046 AN: 4824

European-Finnish (FIN) AF: 0.107 AC: 1130 AN: 10596

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.199 AC: 13500 AN: 68000

Other (OTH) AF: 0.188 AC: 398 AN: 2112

Alfa AF: 0.190 Hom.: 2133

Bravo AF: 0.192

TwinsUK AF: 0.193 AC: 714

ALSPAC AF: 0.199 AC: 767

ESP6500AA AF: 0.177 AC: 688

ESP6500EA AF: 0.195 AC: 1621

ExAC AF: 0.175 AC: 21080

Asia WGS AF: 0.142 AC: 491 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.95
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.33
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.071
Sift	Benign	0.072	T
Sift4G	Benign	0.13	T
Vest4		0.15
MPC		0.024
ClinPred		0.0015	T
GERP RS		0.45
gMVP		0.43
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: -1

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

Other links and lift over

dbSNP: rs7312569; hg19: chr12-80747209; COSMIC: COSV54016903; COSMIC: COSV54016903;