19-54162748-T-A

Variant names:

• chr19-54162748-T-A
• rs760008036
• NM_144686.4:c.1427A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_144686.4(TMC4):​c.1427A>T​(p.Gln476Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMC4 NM_144686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.70

Genes affected

TMC4 (HGNC:22998): (transmembrane channel like 4) 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4	c.1427A>T	p.Gln476Leu	missense_variant	Exon 10 of 15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.1445A>T	p.Gln482Leu	missense_variant	Exon 10 of 15		NP_001138775.2
TMC4	XM_011526486.3	c.965A>T	p.Gln322Leu	missense_variant	Exon 7 of 12		XP_011524788.1
TMC4	XR_935741.3	n.1488A>T		non_coding_transcript_exon_variant	Exon 10 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC4	ENST00000619895.5	c.1427A>T	p.Gln476Leu	missense_variant	Exon 10 of 15	1	NM_144686.4	ENSP00000479458.1
TMC4	ENST00000617472.4	c.1445A>T	p.Gln482Leu	missense_variant	Exon 10 of 15	1		ENSP00000477627.1
TMC4	ENST00000613723.4	n.668A>T		non_coding_transcript_exon_variant	Exon 4 of 9	1
TMC4	ENST00000495398.1	n.258A>T		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1445A>T (p.Q482L) alteration is located in exon 10 (coding exon 10) of the TMC4 gene. This alteration results from a A to T substitution at nucleotide position 1445, causing the glutamine (Q) at amino acid position 482 to be replaced by a leucine (L). 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	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	.;T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.30	D
PhyloP100		6.7
PrimateAI	Benign	0.42	T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.82
MutPred		0.73		.;Loss of methylation at K486 (P = 0.0577);
MVP		0.20
ClinPred		1.0	D
GERP RS		4.5
gMVP		0.87
Mutation Taster		=29/71	disease causing

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

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Other links and lift over

dbSNP: rs760008036; hg19: chr19-54666481;