chr19-54173068-T-C

Position:

• chr19-54173068-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000619895.5(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.

• Frequency:
  • Genomes: 𝑓 0.61 (28321 hom., cov: 31)
  • Exomes 𝑓: 0.57 (240734 hom.)
• Consequence: TMC4 ENST00000619895.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06

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 Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC4	NM_144686.4	c.50A>G	p.Glu17Gly	missense_variant	1/15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.50A>G	p.Glu17Gly	missense_variant	1/15		NP_001138775.2
TMC4	XM_011526486.3	c.50A>G	p.Glu17Gly	missense_variant	1/12		XP_011524788.1
TMC4	XR_935741.3	n.93A>G		non_coding_transcript_exon_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC4	ENST00000619895.5	c.50A>G	p.Glu17Gly	missense_variant	1/15	1	NM_144686.4	ENSP00000479458	P1
TMC4	ENST00000617472.4	c.50A>G	p.Glu17Gly	missense_variant	1/15	1		ENSP00000477627
TMC4	ENST00000613492.4	n.93A>G		non_coding_transcript_exon_variant	1/4	3

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

Gnomad4 AFR exome AF: 0.669

Gnomad4 AMR exome AF: 0.664

Gnomad4 ASJ exome AF: 0.665

Gnomad4 EAS exome AF: 0.776

Gnomad4 SAS exome AF: 0.477

Gnomad4 FIN exome AF: 0.607

Gnomad4 NFE exome AF: 0.560

Gnomad4 OTH exome AF: 0.583

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

Gnomad4 AFR AF: 0.664

Gnomad4 AMR AF: 0.638

Gnomad4 ASJ AF: 0.680

Gnomad4 EAS AF: 0.757

Gnomad4 SAS AF: 0.480

Gnomad4 FIN AF: 0.610

Gnomad4 NFE AF: 0.563

Gnomad4 OTH AF: 0.579

Alfa AF: 0.569 Hom.: 40355

Bravo AF: 0.616

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0049	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.027
gMVP		0.11

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs641738; hg19: chr19-54676763;