1-19739960-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_181719.7(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 NM_181719.7 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

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]

ACMG classification

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	UniProt
TMCO4	NM_181719.7	c.1043G>T	p.Gly348Val	missense_variant, splice_region_variant	12/16	ENST00000294543.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMCO4	ENST00000294543.11	c.1043G>T	p.Gly348Val	missense_variant, splice_region_variant	12/16	1	NM_181719.7	P1
TMCO4	ENST00000375127.5	c.1043G>T	p.Gly348Val	missense_variant, splice_region_variant	11/16	1
TMCO4	ENST00000489135.5	n.929G>T		splice_region_variant, non_coding_transcript_exon_variant	8/9	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459610 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726106

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.065	T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
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	D
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

Other links and lift over

dbSNP: rs746269000; hg19: chr1-20066453;