Genetic Variant TMC4:p.Gln647Glu (chr19-54160912-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144686.4(TMC4):c.1939C>G(p.Gln647Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TMC4
NM_144686.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.28

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18509847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4 link	c.1939C>G	p.Gln647Glu	missense_variant	Exon 13 of 15	ENST00000619895.5	NP_653287.2	Q7Z404A0A087WVI4
TMC4	NM_001145303.3 link	c.1957C>G	p.Gln653Glu	missense_variant	Exon 13 of 15		NP_001138775.2	Q7Z404A0A087WT65
TMC4	XM_011526486.3 link	c.1477C>G	p.Gln493Glu	missense_variant	Exon 10 of 12		XP_011524788.1
TMC4	XR_935741.3 link	n.2000C>G		non_coding_transcript_exon_variant	Exon 13 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMC4	ENST00000619895.5 link	c.1939C>G	p.Gln647Glu	missense_variant	Exon 13 of 15	1	NM_144686.4	ENSP00000479458.1	A0A087WVI4
TMC4	ENST00000617472.4 link	c.1957C>G	p.Gln653Glu	missense_variant	Exon 13 of 15	1		ENSP00000477627.1	A0A087WT65
TMC4	ENST00000613723.4 link	n.1180C>G		non_coding_transcript_exon_variant	Exon 7 of 9	1
TMC4	ENST00000615945.4 link	n.61C>G		non_coding_transcript_exon_variant	Exon 1 of 3	2		ENSP00000481392.1	A0A087WXY6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112000

Other (OTH)

AF:

0.0000497

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1957C>G (p.Q653E) alteration is located in exon 13 (coding exon 13) of the TMC4 gene. This alteration results from a C to G substitution at nucleotide position 1957, causing the glutamine (Q) at amino acid position 653 to be replaced by a glutamic acid (E). 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

0.088

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0033

.;T

Eigen

Benign

0.052

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.0038

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.64

PhyloP100

6.3

PrimateAI

Uncertain

0.49

Sift4G

Benign

0.068

T;T

Vest4

0.18

MutPred

0.51

.;Loss of catalytic residue at Q653 (P = 0.1223);

MVP

0.16

ClinPred

0.87

GERP RS

5.1

gMVP

0.52

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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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19-54160912-G-C

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