Genetic Variant TMC7:p.Arg13Lys (chr16-18984101-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024847.4(TMC7):c.38G>A(p.Arg13Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000074 in 1,351,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

TMC7
NM_024847.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.21

Publications

0 publications found

Variant links:

Genes affected

TMC7 (HGNC:23000): (transmembrane channel like 7) Predicted to enable mechanosensitive ion channel activity. Predicted to be involved in ion transmembrane transport. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMC7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0557501).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC7	NM_024847.4 link	c.38G>A	p.Arg13Lys	missense_variant	Exon 1 of 16	ENST00000304381.10	NP_079123.3	Q7Z402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMC7	ENST00000304381.10 link	c.38G>A	p.Arg13Lys	missense_variant	Exon 1 of 16	1	NM_024847.4	ENSP00000304710.5	Q7Z402-1
TMC7	ENST00000569532.5 link	c.38G>A	p.Arg13Lys	missense_variant	Exon 1 of 15	2		ENSP00000455041.1	H3BNW8
TMC7	ENST00000568469.5 link	n.79G>A		non_coding_transcript_exon_variant	Exon 1 of 10	2
TMC7	ENST00000421369.3 link	c.-744G>A		upstream_gene_variant		1		ENSP00000397081.3	Q7Z402-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.40e-7

AC:

AN:

1351070

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

666336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27546

American (AMR)

AF:

0.00

AC:

AN:

32272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24040

East Asian (EAS)

AF:

0.00

AC:

AN:

31838

South Asian (SAS)

AF:

0.00

AC:

AN:

75698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33252

Middle Eastern (MID)

AF:

0.000252

AC:

AN:

3966

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1066162

Other (OTH)

AF:

0.00

AC:

AN:

56296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 19, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.38G>A (p.R13K) alteration is located in exon 1 (coding exon 1) of the TMC7 gene. This alteration results from a G to A substitution at nucleotide position 38, causing the arginine (R) at amino acid position 13 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0015

.;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.95

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.41

T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.056

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.69

.;N

PhyloP100

2.2

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.36

N;N

REVEL

Benign

0.12

Sift

Benign

0.22

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.0

.;B

Vest4

0.15

MutPred

0.16

Gain of ubiquitination at R13 (P = 0.0025);Gain of ubiquitination at R13 (P = 0.0025);

MVP

0.24

MPC

0.26

ClinPred

0.10

GERP RS

2.3

PromoterAI

-0.30

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.32

Mutation Taster

=95/5

polymorphism

(source)

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

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16-18984101-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over