rs777777359

Variant names:

• chr9-72820888-C-T
• rs777777359
• NM_138691.3:c.1810C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_138691.3(TMC1):​c.1810C>T​(p.Arg604*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000547 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TMC1 NM_138691.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.15
• Publications: 9 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-72820888-C-T is Pathogenic according to our data. Variant chr9-72820888-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 242394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1810C>T	p.Arg604*	stop_gained	Exon 20 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.1810C>T	p.Arg604*	stop_gained	Exon 20 of 24	ENSP00000297784.6	Q8TDI8
	TMC1	ENST00000340019.4	TSL:5	c.1810C>T	p.Arg604*	stop_gained	Exon 18 of 22	ENSP00000341433.3	Q8TDI8
	TMC1	ENST00000645208.2		c.1810C>T	p.Arg604*	stop_gained	Exon 19 of 23	ENSP00000494684.1	Q8TDI8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251370 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal recessive nonsyndromic hearing loss 7;C1847626:Autosomal dominant nonsyndromic hearing loss 36 (1)
1	-	-	Hearing loss, autosomal recessive (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		6.2
Vest4		0.96
GERP RS		5.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs777777359; hg19: chr9-75435804; COSMIC: COSV52783432;