Genetic Variant TMC4:p.Val697Met (chr19-54160338-C-T) – 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_144686.4(TMC4):c.2089G>A(p.Val697Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000016 in 1,371,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

TMC4
NM_144686.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.35

Publications

0 publications found

Variant links:

Genes affected

TMC4 (HGNC:22998): (transmembrane channel like 4) Predicted to enable mechanosensitive ion channel activity. Predicted to be involved in ion transmembrane transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

TMC4 links:

Genome browser will be placed here

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=0.2694683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4 link	c.2089G>A	p.Val697Met	missense_variant	Exon 15 of 15	ENST00000619895.5	NP_653287.2	Q7Z404A0A087WVI4
TMC4	NM_001145303.3 link	c.2107G>A	p.Val703Met	missense_variant	Exon 15 of 15		NP_001138775.2	Q7Z404A0A087WT65
TMC4	XM_011526486.3 link	c.1627G>A	p.Val543Met	missense_variant	Exon 12 of 12		XP_011524788.1
TMC4	XR_935741.3 link	n.2215G>A		non_coding_transcript_exon_variant	Exon 15 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC4	ENST00000619895.5 link	c.2089G>A	p.Val697Met	missense_variant	Exon 15 of 15	1	NM_144686.4	ENSP00000479458.1		A0A087WVI4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

181898

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000160

AC:

AN:

1371288

Hom.:

Cov.:

AF XY:

0.0000119

AC XY:

AN XY:

672798

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30340

American (AMR)

AF:

0.00

AC:

AN:

30008

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20294

East Asian (EAS)

AF:

0.00

AC:

AN:

38842

South Asian (SAS)

AF:

0.00

AC:

AN:

72358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4578

European-Non Finnish (NFE)

AF:

0.0000197

AC:

AN:

1068314

Other (OTH)

AF:

0.0000178

AC:

AN:

56290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2107G>A (p.V703M) alteration is located in exon 15 (coding exon 15) of the TMC4 gene. This alteration results from a G to A substitution at nucleotide position 2107, causing the valine (V) at amino acid position 703 to be replaced by a methionine (M). 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

0.18

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

.;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.85

T;T

M_CAP

Benign

0.0085

MetaRNN

Benign

0.27

T;T

MetaSVM

Uncertain

-0.066

PhyloP100

2.3

PrimateAI

Benign

0.46

Sift4G

Pathogenic

0.0

D;D

Vest4

0.33

MVP

0.030

ClinPred

0.93

GERP RS

5.4

gMVP

0.20

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr19-54160338-C-T

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