chr19-54161205-G-T

Variant names:

• chr19-54161205-G-T
• rs771715265
• NM_144686.4:c.1742C>A

Variant summary

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

The NM_144686.4(TMC4):​c.1742C>A​(p.Ala581Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,166 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A581V) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TMC4 NM_144686.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• 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 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.1742C>A	p.Ala581Glu	missense_variant	Exon 12 of 15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.1760C>A	p.Ala587Glu	missense_variant	Exon 12 of 15		NP_001138775.2
TMC4	XM_011526486.3	c.1280C>A	p.Ala427Glu	missense_variant	Exon 9 of 12		XP_011524788.1
TMC4	XR_935741.3	n.1803C>A		non_coding_transcript_exon_variant	Exon 12 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC4	ENST00000619895.5	c.1742C>A	p.Ala581Glu	missense_variant	Exon 12 of 15	1	NM_144686.4	ENSP00000479458.1
TMC4	ENST00000617472.4	c.1760C>A	p.Ala587Glu	missense_variant	Exon 12 of 15	1		ENSP00000477627.1
TMC4	ENST00000613723.4	n.983C>A		non_coding_transcript_exon_variant	Exon 6 of 9	1
TMC4	ENST00000615945.4	n.-233C>A		upstream_gene_variant		2		ENSP00000481392.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 39

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.0069	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.62	T
PhyloP100		1.0
PrimateAI	Benign	0.33	T
Sift4G	Uncertain	0.011	D;D
Vest4		0.48
MutPred		0.73		.;Loss of sheet (P = 0.0817);
MVP		0.055
ClinPred		0.94	D
GERP RS		-0.23
gMVP		0.82
Mutation Taster		=79/21	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

Other links and lift over

dbSNP: rs771715265; hg19: chr19-54664942;