19-54162758-C-T

Variant names:

• chr19-54162758-C-T
• rs112014947
• NM_144686.4:c.1417G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144686.4(TMC4):​c.1417G>A​(p.Val473Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMC4 NM_144686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16037583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4	c.1417G>A	p.Val473Ile	missense_variant	Exon 10 of 15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.1435G>A	p.Val479Ile	missense_variant	Exon 10 of 15		NP_001138775.2
TMC4	XM_011526486.3	c.955G>A	p.Val319Ile	missense_variant	Exon 7 of 12		XP_011524788.1
TMC4	XR_935741.3	n.1478G>A		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.1417G>A	p.Val473Ile	missense_variant	Exon 10 of 15	1	NM_144686.4	ENSP00000479458.1
TMC4	ENST00000617472.4	c.1435G>A	p.Val479Ile	missense_variant	Exon 10 of 15	1		ENSP00000477627.1
TMC4	ENST00000613723.4	n.658G>A		non_coding_transcript_exon_variant	Exon 4 of 9	1
TMC4	ENST00000495398.1	n.248G>A		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461736 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1435G>A (p.V479I) alteration is located in exon 10 (coding exon 10) of the TMC4 gene. This alteration results from a G to A substitution at nucleotide position 1435, causing the valine (V) at amino acid position 479 to be replaced by an isoleucine (I). 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	0.080
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.0054	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.51	T;T
Vest4		0.26
MutPred		0.35		.;Gain of catalytic residue at V479 (P = 0.2537);
MVP		0.030
ClinPred		0.92	D
GERP RS		-0.99
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs112014947; hg19: chr19-54666491;