19-54162245-C-T

Variant names:

• chr19-54162245-C-T
• NM_144686.4:c.1543G>A

Variant summary

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

The NM_144686.4(TMC4):​c.1543G>A​(p.Ala515Thr) 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. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 27)
• Consequence: TMC4 NM_144686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.403

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

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=0.05743599).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4	c.1543G>A	p.Ala515Thr	missense_variant	Exon 11 of 15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.1561G>A	p.Ala521Thr	missense_variant	Exon 11 of 15		NP_001138775.2
TMC4	XM_011526486.3	c.1081G>A	p.Ala361Thr	missense_variant	Exon 8 of 12		XP_011524788.1
TMC4	XR_935741.3	n.1604G>A		non_coding_transcript_exon_variant	Exon 11 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC4	ENST00000619895.5	c.1543G>A	p.Ala515Thr	missense_variant	Exon 11 of 15	1	NM_144686.4	ENSP00000479458.1
TMC4	ENST00000617472.4	c.1561G>A	p.Ala521Thr	missense_variant	Exon 11 of 15	1		ENSP00000477627.1
TMC4	ENST00000613723.4	n.784G>A		non_coding_transcript_exon_variant	Exon 5 of 9	1
TMC4	ENST00000495398.1	n.374G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1561G>A (p.A521T) alteration is located in exon 11 (coding exon 11) of the TMC4 gene. This alteration results from a G to A substitution at nucleotide position 1561, causing the alanine (A) at amino acid position 521 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	0.094
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.43	T;T
Vest4		0.079
MutPred		0.31		.;Gain of phosphorylation at A521 (P = 0.1191);
MVP		0.040
ClinPred		0.13	T
GERP RS		-2.7
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-54665981;