16-19463840-C-T

Variant names:

• chr16-19463840-C-T
• rs190728673
• NM_001261841.2:c.1301C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001261841.2(TMC5):​c.1301C>T​(p.Thr434Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: TMC5 NM_001261841.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85
• Publications: 2 publications found

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]

ENSG00000260592 (HGNC:58394):

ACMG classification

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=0.38206196).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC5	NM_001261841.2	MANE Select	c.1301C>T	p.Thr434Met	missense	Exon 8 of 22	NP_001248770.1	Q6UXY8-1
	TMC5	NM_001105248.1		c.1301C>T	p.Thr434Met	missense	Exon 8 of 22	NP_001098718.1	Q6UXY8-1
	TMC5	NM_001308161.1		c.1301C>T	p.Thr434Met	missense	Exon 8 of 21	NP_001295090.1	Q6UXY8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC5	ENST00000542583.7	TSL:2 MANE Select	c.1301C>T	p.Thr434Met	missense	Exon 8 of 22	ENSP00000446274.2	Q6UXY8-1
	TMC5	ENST00000381414.8	TSL:1	c.1301C>T	p.Thr434Met	missense	Exon 8 of 21	ENSP00000370822.4	Q6UXY8-2
	TMC5	ENST00000219821.9	TSL:1	c.563C>T	p.Thr188Met	missense	Exon 4 of 18	ENSP00000219821.5	Q6UXY8-3

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251400 AF XY: 0.0000515

Gnomad AFR exome AF: 0.000123

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: 0.0000792

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000855 AC: 125 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.0000839 AC XY: 61 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000107 AC: 119 AN: 1111980

Other (OTH) AF: 0.0000662 AC: 4 AN: 60394

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74468

African (AFR) AF: 0.000168 AC: 7 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.055
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.8
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.24
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.62
MPC		0.65
ClinPred		0.45	T
GERP RS		3.6
Varity_R		0.050
gMVP		0.49
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs190728673; hg19: chr16-19475162;