1-19694504-A-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.1430T>A(p.Leu477His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,770 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: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TMCO4 NM_181719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29

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, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMCO4	NM_181719.7	c.1430T>A	p.Leu477His	missense_variant	15/16	ENST00000294543.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMCO4	ENST00000294543.11	c.1430T>A	p.Leu477His	missense_variant	15/16	1	NM_181719.7	P1
TMCO4	ENST00000375127.5	c.1430T>A	p.Leu477His	missense_variant	14/16	1
TMCO4	ENST00000489814.5	n.449T>A		non_coding_transcript_exon_variant	4/5	2
TMCO4	ENST00000494342.1	n.491T>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250918 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461770 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 727188

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: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

Feb 27, 2023

The c.1430T>A (p.L477H) alteration is located in exon 15 (coding exon 12) of the TMCO4 gene. This alteration results from a T to A substitution at nucleotide position 1430, causing the leucine (L) at amino acid position 477 to be replaced by a histidine (H). 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	0.31
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.025	D;D
Sift4G	Benign	0.34	T;T
Polyphen		1.0	D;.
Vest4		0.71
MutPred		0.61		Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);
MVP		0.50
MPC		0.58
ClinPred		0.67	D
GERP RS		4.7
Varity_R		0.43
gMVP		0.72

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: rs761729038; hg19: chr1-20020997;