rs2589615

Variant names:

• chr9-72688737-C-T
• rs2589615
• NM_138691.3:c.45C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-72688737-C-T
• chr9-72688737-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_138691.3(TMC1):​c.45C>T​(p.Asp15Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 1,603,854 control chromosomes in the GnomAD database, including 156,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (21222 hom., cov: 32)
  • Exomes 𝑓: 0.43 (135750 hom.)
• Consequence: TMC1 NM_138691.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.92
• Publications: 24 publications found

Genes affected

TMC1 (HGNC:16513): (transmembrane channel like 1) This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness. [provided by RefSeq, Jul 2008]

TMC1 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: Unknown, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 9-72688737-C-T is Benign according to our data. Variant chr9-72688737-C-T is described in ClinVar as Benign. ClinVar VariationId is 47874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138691.3. 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
	TMC1	NM_138691.3	MANE Select	c.45C>T	p.Asp15Asp	synonymous	Exon 6 of 24	NP_619636.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	ENST00000297784.10	TSL:1 MANE Select	c.45C>T	p.Asp15Asp	synonymous	Exon 6 of 24	ENSP00000297784.6	Q8TDI8
	TMC1	ENST00000651183.1		c.-268C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 20	ENSP00000498723.1	A0A494C0T8
	TMC1	ENST00000646619.1		c.-268C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	ENSP00000493726.1	A0A2R8Y434

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77712 AN: 151792 Hom.: 21196 Cov.: 32

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.512

GnomAD2 exomes AF: 0.450 AC: 111050 AN: 246692 AF XY: 0.443

Gnomad AFR exome AF: 0.735

Gnomad AMR exome AF: 0.467

Gnomad ASJ exome AF: 0.461

Gnomad EAS exome AF: 0.421

Gnomad FIN exome AF: 0.435

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.447

GnomAD4 exome AF: 0.427 AC: 620398 AN: 1451946 Hom.: 135750 Cov.: 34 AF XY: 0.427 AC XY: 308382 AN XY: 722558

African (AFR) AF: 0.739 AC: 24580 AN: 33260

American (AMR) AF: 0.469 AC: 20787 AN: 44320

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 11897 AN: 26016

East Asian (EAS) AF: 0.441 AC: 17410 AN: 39464

South Asian (SAS) AF: 0.430 AC: 36838 AN: 85736

European-Finnish (FIN) AF: 0.438 AC: 23329 AN: 53216

Middle Eastern (MID) AF: 0.495 AC: 2842 AN: 5744

European-Non Finnish (NFE) AF: 0.413 AC: 455764 AN: 1104090

Other (OTH) AF: 0.448 AC: 26951 AN: 60100

GnomAD4 genome AF: 0.512 AC: 77789 AN: 151908 Hom.: 21222 Cov.: 32 AF XY: 0.510 AC XY: 37819 AN XY: 74206

African (AFR) AF: 0.724 AC: 30023 AN: 41470

American (AMR) AF: 0.462 AC: 7034 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1629 AN: 3468

East Asian (EAS) AF: 0.431 AC: 2229 AN: 5168

South Asian (SAS) AF: 0.443 AC: 2128 AN: 4806

European-Finnish (FIN) AF: 0.424 AC: 4456 AN: 10518

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.422 AC: 28643 AN: 67918

Other (OTH) AF: 0.513 AC: 1086 AN: 2116

Alfa AF: 0.450 Hom.: 11056

Bravo AF: 0.525

Asia WGS AF: 0.458 AC: 1592 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Autosomal dominant nonsyndromic hearing loss 36 (2)
-	-	2	Autosomal recessive nonsyndromic hearing loss 7 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.8
DANN	Benign	0.47
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2589615; hg19: chr9-75303653; COSMIC: COSV52767123;