19-54160516-G-A

Variant names:

• chr19-54160516-G-A
• NM_144686.4:c.2003C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_144686.4(TMC4):​c.2003C>T​(p.Ala668Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC4 NM_144686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4	c.2003C>T	p.Ala668Val	missense_variant	Exon 14 of 15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.2021C>T	p.Ala674Val	missense_variant	Exon 14 of 15		NP_001138775.2
TMC4	XM_011526486.3	c.1541C>T	p.Ala514Val	missense_variant	Exon 11 of 12		XP_011524788.1
TMC4	XR_935741.3	n.2129C>T		non_coding_transcript_exon_variant	Exon 14 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC4	ENST00000619895.5	c.2003C>T	p.Ala668Val	missense_variant	Exon 14 of 15	1	NM_144686.4	ENSP00000479458.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2021C>T (p.A674V) alteration is located in exon 14 (coding exon 14) of the TMC4 gene. This alteration results from a C to T substitution at nucleotide position 2021, causing the alanine (A) at amino acid position 674 to be replaced by a valine (V). 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	0.33
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.071	.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.055	D
PhyloP100		3.3
PrimateAI	Uncertain	0.59	T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.54
MutPred		0.40		.;Gain of MoRF binding (P = 0.1296);
MVP		0.17
ClinPred		0.99	D
GERP RS		4.4
gMVP		0.69
Mutation Taster		=65/35	polymorphism

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: chr19-54664253;