chr15-81332790-A-T

Variant names:

• chr15-81332790-A-T
• NM_001080532.3:c.2932T>A

Variant summary

Our verdict is Likely benign. The variant received -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. 17/22 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
• 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: Likely_benign. The variant received -2 ACMG points.

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

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.2932T>A	p.Ser978Thr	missense	Exon 22 of 22	NP_001074001.1	Q7Z5M5-1
	TMC3-AS1	NR_120365.1		n.426+249A>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.2932T>A	p.Ser978Thr	missense	Exon 22 of 22	ENSP00000352413.5	Q7Z5M5-1
	TMC3	ENST00000558726.5	TSL:5	c.2935T>A	p.Ser979Thr	missense	Exon 22 of 22	ENSP00000452681.1	H0YK69
	TMC3-AS1	ENST00000829113.1		n.699A>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 81

GnomAD4 genome Cov.: 32

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	0.073
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
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	N
PhyloP100		-0.11
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.075
Sift	Benign	0.49	T
Sift4G	Benign	1.0	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

Other links and lift over

hg19: chr15-81625131;