Genetic Variant TMC4:p.Glu17Gly (chr19-54173068-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_144686.4(TMC4):c.50A>G(p.Glu17Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,613,078 control chromosomes in the GnomAD database, including 269,055 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.61 ( 28321 hom., cov: 31)

Exomes 𝑓: 0.57 ( 240734 hom. )

Consequence

TMC4
NM_144686.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.06

Publications

459 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048981905).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4 link	c.50A>G	p.Glu17Gly	missense_variant	Exon 1 of 15	ENST00000619895.5	NP_653287.2	Q7Z404A0A087WVI4
TMC4	NM_001145303.3 link	c.50A>G	p.Glu17Gly	missense_variant	Exon 1 of 15		NP_001138775.2	Q7Z404A0A087WT65
TMC4	XM_011526486.3 link	c.50A>G	p.Glu17Gly	missense_variant	Exon 1 of 12		XP_011524788.1
TMC4	XR_935741.3 link	n.93A>G		non_coding_transcript_exon_variant	Exon 1 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMC4	ENST00000619895.5 link	c.50A>G	p.Glu17Gly	missense_variant	Exon 1 of 15	1	NM_144686.4	ENSP00000479458.1	A0A087WVI4
TMC4	ENST00000617472.4 link	c.50A>G	p.Glu17Gly	missense_variant	Exon 1 of 15	1		ENSP00000477627.1	A0A087WT65
TMC4	ENST00000613492.4 link	n.93A>G		non_coding_transcript_exon_variant	Exon 1 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.609

AC:

92316

AN:

151704

Hom.:

28278

Cov.:

show subpopulations

Gnomad AFR

AF:

0.664

Gnomad AMI

AF:

0.651

Gnomad AMR

AF:

0.638

Gnomad ASJ

AF:

0.680

Gnomad EAS

AF:

0.757

Gnomad SAS

AF:

0.479

Gnomad FIN

AF:

0.610

Gnomad MID

AF:

0.528

Gnomad NFE

AF:

0.563

Gnomad OTH

AF:

0.581

GnomAD4 exome

AF:

0.571

AC:

834788

AN:

1461254

Hom.:

240734

Cov.:

AF XY:

0.567

AC XY:

412256

AN XY:

726992

show subpopulations

African (AFR)

AF:

0.669

AC:

22368

AN:

33456

American (AMR)

AF:

0.664

AC:

29663

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.665

AC:

17368

AN:

26110

East Asian (EAS)

AF:

0.776

AC:

30764

AN:

39638

South Asian (SAS)

AF:

0.477

AC:

41084

AN:

86212

European-Finnish (FIN)

AF:

0.607

AC:

32384

AN:

53352

Middle Eastern (MID)

AF:

0.499

AC:

2877

AN:

5764

European-Non Finnish (NFE)

AF:

0.560

AC:

623085

AN:

1111698

Other (OTH)

AF:

0.583

AC:

35195

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

19698

39397

59095

78794

98492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17522

35044

52566

70088

87610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.609

AC:

92419

AN:

151824

Hom.:

28321

Cov.:

AF XY:

0.609

AC XY:

45193

AN XY:

74182

show subpopulations

African (AFR)

AF:

0.664

AC:

27515

AN:

41424

American (AMR)

AF:

0.638

AC:

9732

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.680

AC:

2356

AN:

3466

East Asian (EAS)

AF:

0.757

AC:

3862

AN:

5102

South Asian (SAS)

AF:

0.480

AC:

2315

AN:

4824

European-Finnish (FIN)

AF:

0.610

AC:

6437

AN:

10550

Middle Eastern (MID)

AF:

0.544

AC:

160

AN:

294

European-Non Finnish (NFE)

AF:

0.563

AC:

38230

AN:

67888

Other (OTH)

AF:

0.579

AC:

1222

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1905

3810

5715

7620

9525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

760

1520

2280

3040

3800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.578

Hom.:

96546

Bravo

AF:

0.616

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.31

(source)

DEOGEN2

Benign

0.0017

.;T

LIST_S2

Benign

0.083

T;T

MetaRNN

Benign

0.0049

T;T

PhyloP100

-1.1

Sift4G

Benign

1.0

T;T

Vest4

0.027

PromoterAI

0.059

Neutral

(source)

gMVP

0.11

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over