rs114495857

Variant names:

• chr19-54171960-T-C
• rs114495857
• NM_144686.4:c.203A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_144686.4(TMC4):​c.203A>G​(p.Lys68Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 1,613,676 control chromosomes in the GnomAD database, including 21 homozygotes. 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 Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (20 hom.)
• Consequence: TMC4 NM_144686.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.242

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051670074).
• BP6: Variant 19-54171960-T-C is Benign according to our data. Variant chr19-54171960-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3038372.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC4	NM_144686.4	c.203A>G	p.Lys68Arg	missense_variant	Exon 2 of 15	ENST00000619895.5	NP_653287.2
TMC4	NM_001145303.3	c.221A>G	p.Lys74Arg	missense_variant	Exon 2 of 15		NP_001138775.2
TMC4	XM_011526486.3	c.221A>G	p.Lys74Arg	missense_variant	Exon 2 of 12		XP_011524788.1
TMC4	XR_935741.3	n.264A>G		non_coding_transcript_exon_variant	Exon 2 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC4	ENST00000619895.5	c.203A>G	p.Lys68Arg	missense_variant	Exon 2 of 15	1	NM_144686.4	ENSP00000479458.1

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 318 AN: 152030 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00238 AC: 598 AN: 250936 AF XY: 0.00260

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00334

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00352

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00319 AC: 4665 AN: 1461528 Hom.: 20 Cov.: 32 AF XY: 0.00322 AC XY: 2338 AN XY: 727052

African (AFR) AF: 0.000597 AC: 20 AN: 33474

American (AMR) AF: 0.00325 AC: 145 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00215 AC: 56 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00108 AC: 93 AN: 86220

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53410

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5760

European-Non Finnish (NFE) AF: 0.00375 AC: 4164 AN: 1111822

Other (OTH) AF: 0.00257 AC: 155 AN: 60366

GnomAD4 genome AF: 0.00209 AC: 318 AN: 152148 Hom.: 1 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74374

African (AFR) AF: 0.000722 AC: 30 AN: 41530

American (AMR) AF: 0.00360 AC: 55 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00312 AC: 212 AN: 67962

Other (OTH) AF: 0.00380 AC: 8 AN: 2106

Alfa AF: 0.00358 Hom.: 3

Bravo AF: 0.00275

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00241 AC: 292

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00452

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TMC4-related disorder Benign:1

Feb 04, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.90
DEOGEN2	Benign	0.0079	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		0.24
PrimateAI	Uncertain	0.51	T
Sift4G	Uncertain	0.047	D;D
Vest4		0.11
MVP		0.15
ClinPred		0.00012	T
GERP RS		1.7
gMVP		0.10
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

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Other links and lift over

dbSNP: rs114495857; hg19: chr19-54675729;