15-81332790-A-T

Position:

• chr15-81332790-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080532.3(TMC3):​c.2932T>A​(p.Ser978Thr) 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. 16/21 in silico tools predict 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: -0.107

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049263507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC3	NM_001080532.3	c.2932T>A	p.Ser978Thr	missense_variant	22/22	ENST00000359440.6	NP_001074001.1
TMC3-AS1	NR_120365.1	n.426+249A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC3	ENST00000359440.6	c.2932T>A	p.Ser978Thr	missense_variant	22/22	1	NM_001080532.3	ENSP00000352413.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 81

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

Mar 18, 2024

The c.2932T>A (p.S978T) alteration is located in exon 22 (coding exon 22) of the TMC3 gene. This alteration results from a T to A substitution at nucleotide position 2932, causing the serine (S) at amino acid position 978 to be replaced by a threonine (T). 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	0.073
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.18
DANN	Benign	0.54
DEOGEN2	Benign	0.0040	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	.;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.080	N;N
REVEL	Benign	0.075
Sift	Benign	0.49	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.065
MutPred		0.13		.;Loss of sheet (P = 0.0817);
MVP		0.12
MPC		0.14
ClinPred		0.056	T
GERP RS		-8.1
Varity_R		0.074
gMVP		0.17

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: chr15-81625131;