rs17058153

chr9-72792243-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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. 12/19 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:7
• Conservation: PhyloP100: 4.64

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 172) in uniprot entity TMC1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_138691.3
• 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 [Likely_benign]. Clinvar id is 47860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-72792243-T-C is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC1	NM_138691.3	c.1457T>C	p.Met486Thr	missense_variant	17/24	ENST00000297784.10
TMC1	XM_017014256.2	c.1460T>C	p.Met487Thr	missense_variant	14/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC1	ENST00000297784.10	c.1457T>C	p.Met486Thr	missense_variant	17/24	1	NM_138691.3	P2

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

GnomAD3 exomes AF: 0.0236 AC: 5945 AN: 251456 Hom.: 124 AF XY: 0.0267 AC XY: 3629 AN XY: 135894

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 SAS exome AF: 0.0610

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

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.00803

Gnomad4 ASJ exome AF: 0.0561

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0620

Gnomad4 FIN exome AF: 0.0240

Gnomad4 NFE exome AF: 0.0212

Gnomad4 OTH exome AF: 0.0245

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

Gnomad4 AFR AF: 0.00378

Gnomad4 AMR AF: 0.00941

Gnomad4 ASJ AF: 0.0631

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0524

Gnomad4 FIN AF: 0.0265

Gnomad4 NFE AF: 0.0227

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0219 Hom.: 117

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

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 13, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 10, 2018	- -

Autosomal dominant nonsyndromic hearing loss 36 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal recessive nonsyndromic hearing loss 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

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;T;.;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.085
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.44	N;N;.;N;.
MutationTaster	Benign	0.80	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N;.;.;N;.
REVEL	Benign	0.047
Sift	Benign	0.25	T;.;.;T;.
Sift4G	Uncertain	0.027	D;.;.;D;.
Polyphen		0.0030	B;B;.;B;.
Vest4		0.13
MPC		0.19
ClinPred		0.0070	T
GERP RS		6.0
Varity_R		0.22
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs17058153; hg19: chr9-75407159;