Genetic Variant TMC5:p.Arg412Leu (chr16-19463366-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001261841.2(TMC5):c.1235G>T(p.Arg412Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R412Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TMC5
NM_001261841.2 missense, splice_region

Scores

Splicing: ADA: 0.0002279

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0390

Publications

0 publications found

Variant links:

Genes affected

TMC5 (HGNC:22999): (transmembrane channel like 5) 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]

TMC5 links:

ENSG00000260592 (HGNC:58394):

ENSG00000260592 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06448957).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001261841.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMC5	NM_001261841.2	MANE Select	c.1235G>T	p.Arg412Leu	missense splice_region	Exon 7 of 22	NP_001248770.1	Q6UXY8-1
TMC5	NM_001105248.1		c.1235G>T	p.Arg412Leu	missense splice_region	Exon 7 of 22	NP_001098718.1	Q6UXY8-1
TMC5	NM_001308161.1		c.1235G>T	p.Arg412Leu	missense splice_region	Exon 7 of 21	NP_001295090.1	Q6UXY8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMC5	ENST00000542583.7	TSL:2 MANE Select	c.1235G>T	p.Arg412Leu	missense splice_region	Exon 7 of 22	ENSP00000446274.2	Q6UXY8-1
TMC5	ENST00000381414.8	TSL:1	c.1235G>T	p.Arg412Leu	missense splice_region	Exon 7 of 21	ENSP00000370822.4	Q6UXY8-2
TMC5	ENST00000219821.9	TSL:1	c.497G>T	p.Arg166Leu	missense splice_region	Exon 3 of 18	ENSP00000219821.5	Q6UXY8-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458522

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725818

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33404

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108928

Other (OTH)

AF:

0.00

AC:

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

3.2

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.00056

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.66

M_CAP

Benign

0.0022

MetaRNN

Benign

0.064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

PhyloP100

0.039

PrimateAI

Benign

0.21

PROVEAN

Benign

2.3

REVEL

Benign

0.081

Sift

Benign

1.0

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.099

MutPred

0.51

Loss of MoRF binding (P = 0.0027)

MVP

0.20

MPC

0.20

ClinPred

0.035

GERP RS

-6.5

Varity_R

0.046

gMVP

0.20

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00023

dbscSNV1_RF

Benign

0.014

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over