chr19-54161156-G-T

Variant names:

• chr19-54161156-G-T
• rs765431768
• NM_144686.4:c.1791C>A

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.1791C>A​(p.Ser597Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,588,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMC4 NM_144686.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.15
• 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=0.18725547).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4	c.1791C>A	p.Ser597Arg	missense_variant	Exon 12 of 15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.1809C>A	p.Ser603Arg	missense_variant	Exon 12 of 15		NP_001138775.2
TMC4	XM_011526486.3	c.1329C>A	p.Ser443Arg	missense_variant	Exon 9 of 12		XP_011524788.1
TMC4	XR_935741.3	n.1852C>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.1791C>A	p.Ser597Arg	missense_variant	Exon 12 of 15	1	NM_144686.4	ENSP00000479458.1
TMC4	ENST00000617472.4	c.1809C>A	p.Ser603Arg	missense_variant	Exon 12 of 15	1		ENSP00000477627.1
TMC4	ENST00000613723.4	n.1032C>A		non_coding_transcript_exon_variant	Exon 6 of 9	1
TMC4	ENST00000615945.4	n.-184C>A		upstream_gene_variant		2		ENSP00000481392.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000444 AC: 1 AN: 225350 AF XY: 0.00000815

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000966

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1436446 Hom.: 0 Cov.: 39 AF XY: 0.00000280 AC XY: 2 AN XY: 713476

African (AFR) AF: 0.00 AC: 0 AN: 31840

American (AMR) AF: 0.00 AC: 0 AN: 38066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39344

South Asian (SAS) AF: 0.00 AC: 0 AN: 83340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1101416

Other (OTH) AF: 0.00 AC: 0 AN: 59120

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74298

African (AFR) AF: 0.0000241 AC: 1 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1809C>A (p.S603R) alteration is located in exon 12 (coding exon 12) of the TMC4 gene. This alteration results from a C to A substitution at nucleotide position 1809, causing the serine (S) at amino acid position 603 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.049
DANN	Benign	0.88
DEOGEN2	Benign	0.067	.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.69	T
PhyloP100		-4.1
PrimateAI	Benign	0.41	T
Sift4G	Uncertain	0.0080	D;D
Vest4		0.38
MutPred		0.73		.;Gain of methylation at S603 (P = 0.026);
MVP		0.067
ClinPred		0.095	T
GERP RS		-9.4
gMVP		0.75
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs765431768; hg19: chr19-54664893;