15-81332798-C-T

Variant names:

• chr15-81332798-C-T
• rs530756760
• NM_001080532.3:c.2924G>A

Variant summary

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

The NM_001080532.3(TMC3):​c.2924G>A​(p.Gly975Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TMC3 NM_001080532.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24
• Publications: 0 publications found

Genes affected

TMC3 (HGNC:22995): (transmembrane channel like 3) Predicted to enable mechanosensitive ion channel activity. Predicted to be involved in ion transmembrane transport. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMC3-AS1 (HGNC:51424): (TMC3 antisense RNA 1)

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=0.2607965).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080532.3. 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
	TMC3	NM_001080532.3	MANE Select	c.2924G>A	p.Gly975Glu	missense	Exon 22 of 22	NP_001074001.1	Q7Z5M5-1
	TMC3-AS1	NR_120365.1		n.426+257C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC3	ENST00000359440.6	TSL:1 MANE Select	c.2924G>A	p.Gly975Glu	missense	Exon 22 of 22	ENSP00000352413.5	Q7Z5M5-1
	TMC3	ENST00000558726.5	TSL:5	c.2927G>A	p.Gly976Glu	missense	Exon 22 of 22	ENSP00000452681.1	H0YK69
	TMC3-AS1	ENST00000829113.1		n.707C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000418 AC: 1 AN: 239366 AF XY: 0.00000766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000579

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1458992 Hom.: 0 Cov.: 81 AF XY: 0.00000276 AC XY: 2 AN XY: 725574

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 85936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110712

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74476

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

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ExAC AF: 0.0000249 AC: 3

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	0.21
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.029	T
Eigen	Benign	0.033
Eigen_PC	Benign	-0.087
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.062	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.91	P
Vest4		0.31
MutPred		0.52		Loss of MoRF binding (P = 0.0852)
MVP		0.77
MPC		0.67
ClinPred		0.72	D
GERP RS		3.5
Varity_R		0.10
gMVP		0.60

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: rs530756760; hg19: chr15-81625139; COSMIC: COSV63922408; COSMIC: COSV63922408;