9-72740177-C-T

Variant names:

• chr9-72740177-C-T
• rs11143384
• NM_138691.3:c.421C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_138691.3(TMC1):​c.421C>T​(p.Arg141Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00957 in 1,613,376 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0068 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (93 hom.)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.615
• Publications: 17 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):

• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.85843 (below the threshold of 3.09). Trascript score misZ: 1.5687 (below the threshold of 3.09). GenCC associations: The gene is linked to nonsyndromic genetic hearing loss, autosomal recessive nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 36, hearing loss, autosomal recessive, autosomal dominant nonsyndromic hearing loss.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006860882).
• BP6: Variant 9-72740177-C-T is Benign according to our data. Variant chr9-72740177-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47873.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00676 (1028/152066) while in subpopulation NFE AF = 0.0108 (735/67946). AF 95% confidence interval is 0.0102. There are 3 homozygotes in GnomAd4. There are 462 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 SD,AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	NM_138691.3	MANE Select	c.421C>T	p.Arg141Trp	missense	Exon 9 of 24	NP_619636.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC1	ENST00000297784.10	TSL:1 MANE Select	c.421C>T	p.Arg141Trp	missense	Exon 9 of 24	ENSP00000297784.6
	TMC1	ENST00000651183.1		c.-18C>T		5_prime_UTR_premature_start_codon_gain	Exon 6 of 20	ENSP00000498723.1
	TMC1	ENST00000646619.1		c.-18C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 18	ENSP00000493726.1

Frequencies

GnomAD3 genomes AF: 0.00677 AC: 1028 AN: 151948 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00199

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00701 AC: 1763 AN: 251416 AF XY: 0.00709

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00468

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00987 AC: 14417 AN: 1461310 Hom.: 93 Cov.: 30 AF XY: 0.00975 AC XY: 7086 AN XY: 726970

African (AFR) AF: 0.00135 AC: 45 AN: 33456

American (AMR) AF: 0.00447 AC: 200 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 409 AN: 26114

East Asian (EAS) AF: 0.000278 AC: 11 AN: 39594

South Asian (SAS) AF: 0.00528 AC: 455 AN: 86244

European-Finnish (FIN) AF: 0.00281 AC: 150 AN: 53408

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5762

European-Non Finnish (NFE) AF: 0.0114 AC: 12635 AN: 1111646

Other (OTH) AF: 0.00827 AC: 499 AN: 60366

GnomAD4 genome AF: 0.00676 AC: 1028 AN: 152066 Hom.: 3 Cov.: 32 AF XY: 0.00622 AC XY: 462 AN XY: 74324

African (AFR) AF: 0.00186 AC: 77 AN: 41482

American (AMR) AF: 0.00655 AC: 100 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4820

European-Finnish (FIN) AF: 0.00199 AC: 21 AN: 10574

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0108 AC: 735 AN: 67946

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00886 Hom.: 22

Bravo AF: 0.00637

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00953 AC: 82

ExAC AF: 0.00698 AC: 848

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.00871

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 36 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.070	N
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.61
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.14
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.41
MVP		0.64
MPC		0.56
ClinPred		0.022	T
GERP RS		3.7
Varity_R		0.13
gMVP		0.53
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs11143384; hg19: chr9-75355093; COSMIC: COSV52768164; COSMIC: COSV52768164;