1-19746507-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_181719.7(TMCO4):c.706G>A(p.Gly236Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,459,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TMCO4 NM_181719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMCO4	NM_181719.7	c.706G>A	p.Gly236Ser	missense_variant	9/16	ENST00000294543.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMCO4	ENST00000294543.11	c.706G>A	p.Gly236Ser	missense_variant	9/16	1	NM_181719.7	P1
TMCO4	ENST00000375127.5	c.706G>A	p.Gly236Ser	missense_variant	8/16	1
TMCO4	ENST00000489135.5	n.712G>A		non_coding_transcript_exon_variant	6/9	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000163 AC: 4 AN: 245680 Hom.: 0 AF XY: 0.0000225 AC XY: 3 AN XY: 133146

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1459986 Hom.: 0 Cov.: 31 AF XY: 0.00000964 AC XY: 7 AN XY: 726154

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

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

May 30, 2023

The c.706G>A (p.G236S) alteration is located in exon 9 (coding exon 6) of the TMCO4 gene. This alteration results from a G to A substitution at nucleotide position 706, causing the glycine (G) at amino acid position 236 to be replaced by a serine (S). 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	0.21
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.039	D;D
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.81		Gain of glycosylation at G236 (P = 0.0103);Gain of glycosylation at G236 (P = 0.0103);
MVP		0.42
MPC		0.52
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.70
gMVP		0.94

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

Other links and lift over

dbSNP: rs755015270; hg19: chr1-20073000; COSMIC: COSV53874193; COSMIC: COSV53874193;