chr16-19466089-T-G

Variant names:

• chr16-19466089-T-G
• rs1968181551
• NM_001261841.2:c.1493T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001261841.2(TMC5):​c.1493T>G​(p.Phe498Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMC5 NM_001261841.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

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.1493T>G	p.Phe498Cys	missense	Exon 9 of 22	NP_001248770.1	Q6UXY8-1
	TMC5	NM_001105248.1		c.1493T>G	p.Phe498Cys	missense	Exon 9 of 22	NP_001098718.1	Q6UXY8-1
	TMC5	NM_001308161.1		c.1493T>G	p.Phe498Cys	missense	Exon 9 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.1493T>G	p.Phe498Cys	missense	Exon 9 of 22	ENSP00000446274.2	Q6UXY8-1
	TMC5	ENST00000381414.8	TSL:1	c.1493T>G	p.Phe498Cys	missense	Exon 9 of 21	ENSP00000370822.4	Q6UXY8-2
	TMC5	ENST00000219821.9	TSL:1	c.755T>G	p.Phe252Cys	missense	Exon 5 of 18	ENSP00000219821.5	Q6UXY8-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461680 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727134

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

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111898

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.015	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.69		Gain of sheet (P = 0.0827)
MVP		0.72
MPC		0.81
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.95
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1968181551; hg19: chr16-19477411;