19-54173068-T-C

Variant names:

• chr19-54173068-T-C
• rs641738
• NM_144686.4:c.50A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_144686.4(TMC4):​c.50A>G​(p.Glu17Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,613,078 control chromosomes in the GnomAD database, including 269,055 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 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. E17V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.61 (28321 hom., cov: 31)
  • Exomes 𝑓: 0.57 (240734 hom.)
• Consequence: TMC4 NM_144686.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 459 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048981905).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

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.50A>G	p.Glu17Gly	missense	Exon 1 of 15	NP_653287.2	A0A087WVI4
	TMC4	NM_001145303.3		c.50A>G	p.Glu17Gly	missense	Exon 1 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.50A>G	p.Glu17Gly	missense	Exon 1 of 15	ENSP00000479458.1	A0A087WVI4
	TMC4	ENST00000617472.4	TSL:1	c.50A>G	p.Glu17Gly	missense	Exon 1 of 15	ENSP00000477627.1	A0A087WT65
	TMC4	ENST00000883974.1		c.50A>G	p.Glu17Gly	missense	Exon 1 of 15	ENSP00000554033.1

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92316 AN: 151704 Hom.: 28278 Cov.: 31

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.757

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.581

GnomAD4 exome AF: 0.571 AC: 834788 AN: 1461254 Hom.: 240734 Cov.: 52 AF XY: 0.567 AC XY: 412256 AN XY: 726992

African (AFR) AF: 0.669 AC: 22368 AN: 33456

American (AMR) AF: 0.664 AC: 29663 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 17368 AN: 26110

East Asian (EAS) AF: 0.776 AC: 30764 AN: 39638

South Asian (SAS) AF: 0.477 AC: 41084 AN: 86212

European-Finnish (FIN) AF: 0.607 AC: 32384 AN: 53352

Middle Eastern (MID) AF: 0.499 AC: 2877 AN: 5764

European-Non Finnish (NFE) AF: 0.560 AC: 623085 AN: 1111698

Other (OTH) AF: 0.583 AC: 35195 AN: 60364

GnomAD4 genome AF: 0.609 AC: 92419 AN: 151824 Hom.: 28321 Cov.: 31 AF XY: 0.609 AC XY: 45193 AN XY: 74182

African (AFR) AF: 0.664 AC: 27515 AN: 41424

American (AMR) AF: 0.638 AC: 9732 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2356 AN: 3466

East Asian (EAS) AF: 0.757 AC: 3862 AN: 5102

South Asian (SAS) AF: 0.480 AC: 2315 AN: 4824

European-Finnish (FIN) AF: 0.610 AC: 6437 AN: 10550

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38230 AN: 67888

Other (OTH) AF: 0.579 AC: 1222 AN: 2110

Alfa AF: 0.578 Hom.: 96546

Bravo AF: 0.616

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.31
DEOGEN2	Benign	0.0017	T
LIST_S2	Benign	0.083	T
MetaRNN	Benign	0.0049	T
PhyloP100		-1.1
Sift4G	Benign	1.0	T
Vest4		0.027
PromoterAI		0.059	Neutral
gMVP		0.11

Splicing

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

Other links and lift over

dbSNP: rs641738; hg19: chr19-54676763;