19-54162199-A-T

Variant names:

• chr19-54162199-A-T
• NM_144686.4:c.1589T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_144686.4(TMC4):​c.1589T>A​(p.Ile530Asn) 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: 5.79

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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4	c.1589T>A	p.Ile530Asn	missense_variant	Exon 11 of 15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.1607T>A	p.Ile536Asn	missense_variant	Exon 11 of 15		NP_001138775.2
TMC4	XM_011526486.3	c.1127T>A	p.Ile376Asn	missense_variant	Exon 8 of 12		XP_011524788.1
TMC4	XR_935741.3	n.1650T>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.1589T>A	p.Ile530Asn	missense_variant	Exon 11 of 15	1	NM_144686.4	ENSP00000479458.1
TMC4	ENST00000617472.4	c.1607T>A	p.Ile536Asn	missense_variant	Exon 11 of 15	1		ENSP00000477627.1
TMC4	ENST00000613723.4	n.830T>A		non_coding_transcript_exon_variant	Exon 5 of 9	1
TMC4	ENST00000495398.1	n.*27T>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1607T>A (p.I536N) alteration is located in exon 11 (coding exon 11) of the TMC4 gene. This alteration results from a T to A substitution at nucleotide position 1607, causing the isoleucine (I) at amino acid position 536 to be replaced by an asparagine (N). 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	0.76
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	.;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.11	D
PhyloP100		5.8
PrimateAI	Uncertain	0.64	T
Sift4G	Uncertain	0.0020	D;D
Vest4		0.89
MutPred		0.83		.;Loss of stability (P = 0.0972);
MVP		0.35
ClinPred		0.97	D
GERP RS		4.9
gMVP		0.79
Mutation Taster		=46/54	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

hg19: chr19-54665935;