19-54163088-C-G

Variant names:

• chr19-54163088-C-G
• rs116092322
• NM_144686.4:c.1349G>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.1349G>C​(p.Gly450Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G450D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMC4 NM_144686.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.18
• 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=0.2270611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4	c.1349G>C	p.Gly450Ala	missense_variant	Exon 9 of 15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.1367G>C	p.Gly456Ala	missense_variant	Exon 9 of 15		NP_001138775.2
TMC4	XM_011526486.3	c.887G>C	p.Gly296Ala	missense_variant	Exon 6 of 12		XP_011524788.1
TMC4	XR_935741.3	n.1410G>C		non_coding_transcript_exon_variant	Exon 9 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC4	ENST00000619895.5	c.1349G>C	p.Gly450Ala	missense_variant	Exon 9 of 15	1	NM_144686.4	ENSP00000479458.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.041	.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.39	T
PhyloP100		3.2
PrimateAI	Benign	0.41	T
Sift4G	Uncertain	0.045	D;D
Vest4		0.35
MutPred		0.43		.;Loss of disorder (P = 0.1016);
MVP		0.13
ClinPred		0.98	D
GERP RS		4.9
gMVP		0.62
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs116092322; hg19: chr19-54666821;