1-19700774-T-C

Position:

• chr1-19700774-T-C

Variant summary

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

The NM_181719.7(TMCO4):​c.1376A>G​(p.Tyr459Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: TMCO4 NM_181719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25

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, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMCO4	NM_181719.7	c.1376A>G	p.Tyr459Cys	missense_variant	14/16	ENST00000294543.11	NP_859070.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMCO4	ENST00000294543.11	c.1376A>G	p.Tyr459Cys	missense_variant	14/16	1	NM_181719.7	ENSP00000294543.6
TMCO4	ENST00000375127.5	c.1376A>G	p.Tyr459Cys	missense_variant	13/16	1		ENSP00000364269.1
TMCO4	ENST00000489814.5	n.395A>G		non_coding_transcript_exon_variant	3/5	2
TMCO4	ENST00000494342.1	n.437A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Sep 09, 2024

The c.1376A>G (p.Y459C) alteration is located in exon 14 (coding exon 11) of the TMCO4 gene. This alteration results from a A to G substitution at nucleotide position 1376, causing the tyrosine (Y) at amino acid position 459 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	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.00080	D
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.91		Loss of MoRF binding (P = 0.0791);Loss of MoRF binding (P = 0.0791);
MVP		0.91
MPC		0.58
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.90
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-20027267;