15-81332437-C-G

Position:

• chr15-81332437-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080532.3(TMC3):​c.3285G>C​(p.Leu1095Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC3 NM_001080532.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.712

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24961925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC3	NM_001080532.3	c.3285G>C	p.Leu1095Phe	missense_variant	22/22	ENST00000359440.6	NP_001074001.1
TMC3-AS1	NR_120365.1	n.322C>G		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC3	ENST00000359440.6	c.3285G>C	p.Leu1095Phe	missense_variant	22/22	1	NM_001080532.3	ENSP00000352413.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 82

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.3285G>C (p.L1095F) alteration is located in exon 22 (coding exon 22) of the TMC3 gene. This alteration results from a G to C substitution at nucleotide position 3285, causing the leucine (L) at amino acid position 1095 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	.;T
Eigen	Benign	-0.026
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Uncertain	-0.077	T
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.88	N;N
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.25
MutPred		0.23		.;Loss of disorder (P = 0.123);
MVP		0.51
MPC		0.67
ClinPred		0.85	D
GERP RS		2.4
Varity_R		0.16
gMVP		0.050

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-81624778; COSMIC: COSV63923102; COSMIC: COSV63923102;