Genetic Variant NM_024847.4:c.176G>C (chr16-19009280-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_024847.4(TMC7):c.176G>C(p.Arg59Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMC7
NM_024847.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.80

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.41823974).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC7	NM_024847.4 link	c.176G>C	p.Arg59Pro	missense_variant	Exon 2 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.176G>C	p.Arg59Pro	missense_variant	Exon 2 of 16	1	NM_024847.4	ENSP00000304710.5	Q7Z402-1
TMC7	ENST00000421369.3 link	c.-155G>C		5_prime_UTR_variant	Exon 2 of 16	1		ENSP00000397081.3	Q7Z402-2
TMC7	ENST00000569532.5 link	c.176G>C	p.Arg59Pro	missense_variant	Exon 2 of 15	2		ENSP00000455041.1	H3BNW8
TMC7	ENST00000568469.5 link	n.217G>C		non_coding_transcript_exon_variant	Exon 2 of 10	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

.;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.78

T;T

M_CAP

Benign

0.083

MetaRNN

Benign

0.42

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.7

.;L

PhyloP100

2.8

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.2

N;N

REVEL

Uncertain

0.34

Sift

Benign

0.14

T;T

Sift4G

Benign

0.099

T;T

Polyphen

0.44

.;B

Vest4

0.60

MutPred

0.29

Loss of MoRF binding (P = 0.0049);Loss of MoRF binding (P = 0.0049);

MVP

0.33

MPC

0.81

ClinPred

0.62

GERP RS

3.4

Varity_R

0.18

gMVP

0.44

Mutation Taster

=77/23

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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NM_024847.4:c.176G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over