rs17058153

Variant names:

• chr9-72792243-T-C
• rs17058153
• NM_138691.3:c.1457T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-72792243-T-C
• chr9-72792243-T-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_138691.3(TMC1):​c.1457T>C​(p.Met486Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0226 in 1,614,168 control chromosomes in the GnomAD database, including 623 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (33 hom., cov: 32)
  • Exomes 𝑓: 0.023 (590 hom.)
• Consequence: TMC1 NM_138691.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.64
• Publications: 16 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 -19 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=0.0026560128).
• BP6: Variant 9-72792243-T-C is Benign according to our data. Variant chr9-72792243-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0606 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.1457T>C	p.Met486Thr	missense	Exon 17 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.1457T>C	p.Met486Thr	missense	Exon 17 of 24	ENSP00000297784.6
	TMC1	ENST00000340019.4	TSL:5	c.1457T>C	p.Met486Thr	missense	Exon 15 of 22	ENSP00000341433.3
	TMC1	ENST00000645208.2		c.1457T>C	p.Met486Thr	missense	Exon 16 of 23	ENSP00000494684.1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2694 AN: 152194 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.00942

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.0265

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0236 AC: 5945 AN: 251456 AF XY: 0.0267

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.00705

Gnomad ASJ exome AF: 0.0574

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0250

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0231 AC: 33829 AN: 1461856 Hom.: 590 Cov.: 33 AF XY: 0.0247 AC XY: 17978 AN XY: 727228

African (AFR) AF: 0.00323 AC: 108 AN: 33480

American (AMR) AF: 0.00803 AC: 359 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0561 AC: 1466 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.0620 AC: 5346 AN: 86258

European-Finnish (FIN) AF: 0.0240 AC: 1281 AN: 53420

Middle Eastern (MID) AF: 0.0333 AC: 192 AN: 5768

European-Non Finnish (NFE) AF: 0.0212 AC: 23593 AN: 1111984

Other (OTH) AF: 0.0245 AC: 1479 AN: 60394

GnomAD4 genome AF: 0.0177 AC: 2696 AN: 152312 Hom.: 33 Cov.: 32 AF XY: 0.0176 AC XY: 1314 AN XY: 74490

African (AFR) AF: 0.00378 AC: 157 AN: 41574

American (AMR) AF: 0.00941 AC: 144 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 219 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.0524 AC: 253 AN: 4826

European-Finnish (FIN) AF: 0.0265 AC: 281 AN: 10622

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0227 AC: 1541 AN: 68016

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0210 Hom.: 159

Bravo AF: 0.0150

TwinsUK AF: 0.0210 AC: 78

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0259 AC: 223

ExAC AF: 0.0249 AC: 3023

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0244

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	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	0.28
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.085
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.44	N
PhyloP100		4.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.047
Sift	Benign	0.25	T
Sift4G	Uncertain	0.027	D
Polyphen		0.0030	B
Vest4		0.13
MPC		0.19
ClinPred		0.0070	T
GERP RS		6.0
Varity_R		0.22
gMVP		0.80
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs17058153; hg19: chr9-75407159;