Variant chr1-19739960-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000294543.11(TMCO4):c.1043G>T(p.Gly348Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMCO4
ENST00000294543.11 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.46

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMCO4	NM_181719.7 linkuse as main transcript	c.1043G>T	p.Gly348Val	missense_variant, splice_region_variant	12/16	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.1043G>T	p.Gly348Val	missense_variant, splice_region_variant	12/16	1	NM_181719.7	ENSP00000294543.6	Q5TGY1-1
TMCO4	ENST00000375127.5 linkuse as main transcript	c.1043G>T	p.Gly348Val	missense_variant, splice_region_variant	11/16	1		ENSP00000364269.1	A0A075B6H3
TMCO4	ENST00000489135.5 linkuse as main transcript	n.929G>T		splice_region_variant, non_coding_transcript_exon_variant	8/9	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459610

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726106

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Dec 14, 2022

The c.1043G>T (p.G348V) alteration is located in exon 12 (coding exon 9) of the TMCO4 gene. This alteration results from a G to T substitution at nucleotide position 1043, causing the glycine (G) at amino acid position 348 to be replaced by a valine (V). 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

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.065

T;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.034

D;D

Polyphen

1.0

D;.

Vest4

0.99

MutPred

0.82

Loss of glycosylation at S347 (P = 0.029);Loss of glycosylation at S347 (P = 0.029);

MVP

0.59

MPC

0.58

ClinPred

1.0

GERP RS

5.1

Varity_R

0.96

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.37

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.37

Position offset: 0

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