Variant 1-19683384-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181719.7(TMCO4):c.1561C>T(p.Arg521Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000421 in 1,613,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R521H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 1 hom. )

Consequence

TMCO4
NM_181719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.69

Variant links:

Genes affected

TMCO4 (HGNC:27393): (transmembrane and coiled-coil domains 4) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMCO4 links:

TMCO4 (HGNC:):

TMCO4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12233776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMCO4	NM_181719.7 linkuse as main transcript	c.1561C>T	p.Arg521Cys	missense_variant	16/16	ENST00000294543.11	NP_859070.3	Q5TGY1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMCO4	ENST00000294543.11 linkuse as main transcript	c.1561C>T	p.Arg521Cys	missense_variant	16/16	1	NM_181719.7	ENSP00000294543.6	Q5TGY1-1
TMCO4	ENST00000375127.5 linkuse as main transcript	c.1561C>T	p.Arg521Cys	missense_variant	15/16	1		ENSP00000364269.1	A0A075B6H3
TMCO4	ENST00000489814.5 linkuse as main transcript	n.580C>T		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000844

AC:

AN:

248722

Hom.:

AF XY:

0.0000815

AC XY:

AN XY:

134902

show subpopulations

Gnomad AFR exome

AF:

0.0000632

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000708

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000404

AC:

AN:

1461360

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

726996

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2024

The c.1561C>T (p.R521C) alteration is located in exon 16 (coding exon 13) of the TMCO4 gene. This alteration results from a C to T substitution at nucleotide position 1561, causing the arginine (R) at amino acid position 521 to be replaced by a cysteine (C). 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

Benign

0.083

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.055

T;.

Eigen

Benign

0.034

Eigen_PC

Benign

0.031

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-3.8

D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.020

D;D

Polyphen

1.0

D;.

Vest4

0.14

MutPred

0.58

Loss of MoRF binding (P = 0.025);Loss of MoRF binding (P = 0.025);

MVP

0.21

MPC

0.47

ClinPred

0.29

GERP RS

3.2

Varity_R

0.32

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over