19-54160338-C-G

Variant names:

• chr19-54160338-C-G
• rs140744667
• NM_144686.4:c.2089G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144686.4(TMC4):​c.2089G>C​(p.Val697Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,371,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V697M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: TMC4 NM_144686.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• Publications: 0 publications found

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20997792).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144686.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC4	NM_144686.4	MANE Select	c.2089G>C	p.Val697Leu	missense	Exon 15 of 15	NP_653287.2	A0A087WVI4
	TMC4	NM_001145303.3		c.2107G>C	p.Val703Leu	missense	Exon 15 of 15	NP_001138775.2	A0A087WT65

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC4	ENST00000619895.5	TSL:1 MANE Select	c.2089G>C	p.Val697Leu	missense	Exon 15 of 15	ENSP00000479458.1	A0A087WVI4
	TMC4	ENST00000617472.4	TSL:1	c.2107G>C	p.Val703Leu	missense	Exon 15 of 15	ENSP00000477627.1	A0A087WT65
	TMC4	ENST00000613723.4	TSL:1	n.1330G>C		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1371288 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 672798

African (AFR) AF: 0.00 AC: 0 AN: 30340

American (AMR) AF: 0.00 AC: 0 AN: 30008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20294

East Asian (EAS) AF: 0.00 AC: 0 AN: 38842

South Asian (SAS) AF: 0.00 AC: 0 AN: 72358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4578

European-Non Finnish (NFE) AF: 9.36e-7 AC: 1 AN: 1068314

Other (OTH) AF: 0.00 AC: 0 AN: 56290

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.40	T
PhyloP100		2.3
PrimateAI	Benign	0.45	T
Sift4G	Pathogenic	0.0	D
Vest4		0.20
MutPred		0.26		Gain of disorder (P = 0.0832)
MVP		0.030
ClinPred		0.95	D
GERP RS		5.4
gMVP		0.27
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140744667; hg19: chr19-54664075;