19-54160315-C-A

Variant names:

• chr19-54160315-C-A
• rs373451202
• NM_144686.4:c.2112G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_144686.4(TMC4):​c.2112G>T​(p.Pro704Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000733 in 1,363,988 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. Synonymous variant affecting the same amino acid position (i.e. P704P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: TMC4 NM_144686.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.168
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP7: Synonymous conserved (PhyloP=0.168 with no splicing effect.

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.2112G>T	p.Pro704Pro	synonymous	Exon 15 of 15	NP_653287.2	A0A087WVI4
	TMC4	NM_001145303.3		c.2130G>T	p.Pro710Pro	synonymous	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.2112G>T	p.Pro704Pro	synonymous	Exon 15 of 15	ENSP00000479458.1	A0A087WVI4
	TMC4	ENST00000617472.4	TSL:1	c.2130G>T	p.Pro710Pro	synonymous	Exon 15 of 15	ENSP00000477627.1	A0A087WT65
	TMC4	ENST00000613723.4	TSL:1	n.1353G>T		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000560 AC: 1 AN: 178640 AF XY: 0.0000106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000632

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1363988 Hom.: 0 Cov.: 29 AF XY: 0.00000150 AC XY: 1 AN XY: 668562

African (AFR) AF: 0.00 AC: 0 AN: 30120

American (AMR) AF: 0.00 AC: 0 AN: 29034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20038

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38766

South Asian (SAS) AF: 0.00 AC: 0 AN: 70794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4162

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065112

Other (OTH) AF: 0.00 AC: 0 AN: 55942

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.5
DANN	Benign	0.68
PhyloP100		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs373451202; hg19: chr19-54664052;