Genetic Variant NM_144686.4:c.2089G>A (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

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:

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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=0.2694683).

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

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NM_144686.4:c.2089G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over