rs142366138

Variant names:

• chr16-19460325-G-A
• rs142366138
• NM_001261841.2:c.1139G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001261841.2(TMC5):​c.1139G>A​(p.Arg380Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00367 in 1,612,256 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (14 hom.)
• Consequence: TMC5 NM_001261841.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.28
• Publications: 3 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042259097).
• BP6: Variant 16-19460325-G-A is Benign according to our data. Variant chr16-19460325-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2646275.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

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.1139G>A	p.Arg380Lys	missense	Exon 6 of 22	NP_001248770.1	Q6UXY8-1
	TMC5	NM_001105248.1		c.1139G>A	p.Arg380Lys	missense	Exon 6 of 22	NP_001098718.1	Q6UXY8-1
	TMC5	NM_001308161.1		c.1139G>A	p.Arg380Lys	missense	Exon 6 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.1139G>A	p.Arg380Lys	missense	Exon 6 of 22	ENSP00000446274.2	Q6UXY8-1
	TMC5	ENST00000381414.8	TSL:1	c.1139G>A	p.Arg380Lys	missense	Exon 6 of 21	ENSP00000370822.4	Q6UXY8-2
	TMC5	ENST00000219821.9	TSL:1	c.401G>A	p.Arg134Lys	missense	Exon 2 of 18	ENSP00000219821.5	Q6UXY8-3

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 378 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00429

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00220 AC: 551 AN: 250734 AF XY: 0.00238

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00380 AC: 5544 AN: 1459974 Hom.: 14 Cov.: 29 AF XY: 0.00369 AC XY: 2681 AN XY: 726434

African (AFR) AF: 0.000508 AC: 17 AN: 33446

American (AMR) AF: 0.00132 AC: 59 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86114

European-Finnish (FIN) AF: 0.000862 AC: 46 AN: 53364

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00462 AC: 5130 AN: 1110608

Other (OTH) AF: 0.00395 AC: 238 AN: 60292

GnomAD4 genome AF: 0.00248 AC: 378 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00244 AC XY: 182 AN XY: 74452

African (AFR) AF: 0.000818 AC: 34 AN: 41570

American (AMR) AF: 0.00229 AC: 35 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00429 AC: 292 AN: 68022

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00338 Hom.: 9

Bravo AF: 0.00250

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00227 AC: 275

EpiCase AF: 0.00557

EpiControl AF: 0.00332

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.10	T
Sift4G	Benign	0.27	T
Polyphen		0.64	P
Vest4		0.18
MVP		0.46
MPC		0.30
ClinPred		0.012	T
GERP RS		5.3
Varity_R		0.24
gMVP		0.49
Mutation Taster		=96/4	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: rs142366138; hg19: chr16-19471647;