NM_138691.3:c.241G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_138691.3(TMC1):​c.241G>A​(p.Glu81Lys) variant causes a missense change. The variant allele was found at a frequency of 0.192 in 1,586,800 control chromosomes in the GnomAD database, including 32,970 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4128 hom., cov: 29)
Exomes 𝑓: 0.19 ( 28842 hom. )

Consequence

TMC1
NM_138691.3 missense

Scores

3
15

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.72

Publications

34 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.002365142).
BP6
Variant 9-72700522-G-A is Benign according to our data. Variant chr9-72700522-G-A is described in ClinVar as Benign. ClinVar VariationId is 47869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMC1NM_138691.3 linkc.241G>A p.Glu81Lys missense_variant Exon 8 of 24 ENST00000297784.10 NP_619636.2 Q8TDI8
TMC1XM_017014256.2 linkc.244G>A p.Glu82Lys missense_variant Exon 5 of 21 XP_016869745.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMC1ENST00000297784.10 linkc.241G>A p.Glu81Lys missense_variant Exon 8 of 24 1 NM_138691.3 ENSP00000297784.6 Q8TDI8

Frequencies

GnomAD3 genomes
AF:
0.224
AC:
33917
AN:
151144
Hom.:
4116
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.268
Gnomad AMI
AF:
0.153
Gnomad AMR
AF:
0.267
Gnomad ASJ
AF:
0.295
Gnomad EAS
AF:
0.385
Gnomad SAS
AF:
0.328
Gnomad FIN
AF:
0.228
Gnomad MID
AF:
0.220
Gnomad NFE
AF:
0.166
Gnomad OTH
AF:
0.213
GnomAD2 exomes
AF:
0.241
AC:
59211
AN:
245954
AF XY:
0.238
show subpopulations
Gnomad AFR exome
AF:
0.272
Gnomad AMR exome
AF:
0.343
Gnomad ASJ exome
AF:
0.277
Gnomad EAS exome
AF:
0.387
Gnomad FIN exome
AF:
0.230
Gnomad NFE exome
AF:
0.164
Gnomad OTH exome
AF:
0.221
GnomAD4 exome
AF:
0.188
AC:
269945
AN:
1435538
Hom.:
28842
Cov.:
28
AF XY:
0.191
AC XY:
136785
AN XY:
714872
show subpopulations
African (AFR)
AF:
0.270
AC:
8788
AN:
32490
American (AMR)
AF:
0.329
AC:
14306
AN:
43436
Ashkenazi Jewish (ASJ)
AF:
0.275
AC:
6993
AN:
25398
East Asian (EAS)
AF:
0.398
AC:
15382
AN:
38672
South Asian (SAS)
AF:
0.311
AC:
26269
AN:
84400
European-Finnish (FIN)
AF:
0.234
AC:
12114
AN:
51848
Middle Eastern (MID)
AF:
0.202
AC:
1135
AN:
5626
European-Non Finnish (NFE)
AF:
0.158
AC:
172758
AN:
1094748
Other (OTH)
AF:
0.207
AC:
12200
AN:
58920
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
7267
14534
21801
29068
36335
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
6426
12852
19278
25704
32130
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.224
AC:
33952
AN:
151262
Hom.:
4128
Cov.:
29
AF XY:
0.230
AC XY:
16986
AN XY:
73878
show subpopulations
African (AFR)
AF:
0.268
AC:
11050
AN:
41282
American (AMR)
AF:
0.267
AC:
4067
AN:
15206
Ashkenazi Jewish (ASJ)
AF:
0.295
AC:
1023
AN:
3466
East Asian (EAS)
AF:
0.385
AC:
1978
AN:
5142
South Asian (SAS)
AF:
0.329
AC:
1583
AN:
4808
European-Finnish (FIN)
AF:
0.228
AC:
2332
AN:
10242
Middle Eastern (MID)
AF:
0.214
AC:
63
AN:
294
European-Non Finnish (NFE)
AF:
0.166
AC:
11258
AN:
67808
Other (OTH)
AF:
0.218
AC:
459
AN:
2104
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.529
Heterozygous variant carriers
0
1309
2618
3928
5237
6546
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
352
704
1056
1408
1760
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.187
Hom.:
9943
Bravo
AF:
0.225
TwinsUK
AF:
0.160
AC:
595
ALSPAC
AF:
0.154
AC:
592
ESP6500AA
AF:
0.263
AC:
1157
ESP6500EA
AF:
0.169
AC:
1449
ExAC
AF:
0.238
AC:
28859
Asia WGS
AF:
0.343
AC:
1189
AN:
3472

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 23, 2009
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 09, 2017
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Autosomal dominant nonsyndromic hearing loss 36 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal recessive nonsyndromic hearing loss 7 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T;T;T
Eigen
Benign
0.010
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.70
.;.;T
MetaRNN
Benign
0.0024
T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.81
L;L;L
PhyloP100
5.7
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-1.9
N;.;N
REVEL
Benign
0.079
Sift
Benign
0.26
T;.;T
Sift4G
Benign
0.10
T;.;T
Polyphen
0.15
B;B;B
Vest4
0.10
MPC
0.19
ClinPred
0.015
T
GERP RS
5.5
Varity_R
0.32
gMVP
0.40
Mutation Taster
=96/4
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

Publications

Other links and lift over

dbSNP: rs1796993; hg19: chr9-75315438; COSMIC: COSV52781375; API