1-19683150-C-A

Variant names:

• chr1-19683150-C-A
• NM_181719.7:c.1795G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181719.7(TMCO4):​c.1795G>T​(p.Ala599Ser) 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 benign outcome for this variant. 15/21 in silico tools predict a benign 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: -0.102

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057148397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMCO4	NM_181719.7	c.1795G>T	p.Ala599Ser	missense_variant	Exon 16 of 16	ENST00000294543.11	NP_859070.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMCO4	ENST00000294543.11	c.1795G>T	p.Ala599Ser	missense_variant	Exon 16 of 16	1	NM_181719.7	ENSP00000294543.6
TMCO4	ENST00000375127.5	c.1657+138G>T		intron_variant	Intron 15 of 15	1		ENSP00000364269.1
TMCO4	ENST00000489814.5	n.814G>T		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1795G>T (p.A599S) alteration is located in exon 16 (coding exon 13) of the TMCO4 gene. This alteration results from a G to T substitution at nucleotide position 1795, causing the alanine (A) at amino acid position 599 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	0.084
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.1
DANN	Benign	0.90
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.015
Sift	Benign	0.41	T
Sift4G	Benign	0.18	T
Polyphen		0.099	B
Vest4		0.11
MutPred		0.18		Gain of glycosylation at A599 (P = 0.0017);
MVP		0.014
MPC		0.093
ClinPred		0.092	T
GERP RS		2.6
Varity_R		0.031
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-20009643;