NM_001261841.2:c.1555G>C

Variant names:

• chr16-19466151-G-C
• rs760586337
• NM_001261841.2:c.1555G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001261841.2(TMC5):​c.1555G>C​(p.Gly519Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMC5 NM_001261841.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13657787).

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.1555G>C	p.Gly519Arg	missense	Exon 9 of 22	NP_001248770.1	Q6UXY8-1
	TMC5	NM_001105248.1		c.1555G>C	p.Gly519Arg	missense	Exon 9 of 22	NP_001098718.1	Q6UXY8-1
	TMC5	NM_001308161.1		c.1555G>C	p.Gly519Arg	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.1555G>C	p.Gly519Arg	missense	Exon 9 of 22	ENSP00000446274.2	Q6UXY8-1
	TMC5	ENST00000381414.8	TSL:1	c.1555G>C	p.Gly519Arg	missense	Exon 9 of 21	ENSP00000370822.4	Q6UXY8-2
	TMC5	ENST00000219821.9	TSL:1	c.817G>C	p.Gly273Arg	missense	Exon 5 of 18	ENSP00000219821.5	Q6UXY8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251460 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000547158), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.9
DANN	Benign	0.56
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.062
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.084
Sift	Benign	0.098	T
Sift4G	Benign	0.34	T
Polyphen		0.085	B
Vest4		0.32
MutPred		0.40		Gain of methylation at G519 (P = 0.01)
MVP		0.26
MPC		0.20
ClinPred		0.039	T
GERP RS		-1.3
Varity_R		0.094
gMVP		0.77
Mutation Taster		=87/13	polymorphism

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: rs760586337; hg19: chr16-19477473;