rs754745907

Variant names:

• chr1-19683393-C-A
• rs754745907
• NM_181719.7:c.1552G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-19683393-C-A
• chr1-19683393-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181719.7(TMCO4):​c.1552G>T​(p.Val518Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V518M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TMCO4 NM_181719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.03
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO4	NM_181719.7	MANE Select	c.1552G>T	p.Val518Leu	missense	Exon 16 of 16	NP_859070.3
	TMCO4	NM_001349112.3		c.1552G>T	p.Val518Leu	missense	Exon 15 of 15	NP_001336041.1	Q5TGY1-1
	TMCO4	NM_001349113.3		c.1552G>T	p.Val518Leu	missense	Exon 16 of 16	NP_001336042.1	Q5TGY1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMCO4	ENST00000294543.11	TSL:1 MANE Select	c.1552G>T	p.Val518Leu	missense	Exon 16 of 16	ENSP00000294543.6	Q5TGY1-1
	TMCO4	ENST00000375127.5	TSL:1	c.1552G>T	p.Val518Leu	missense	Exon 15 of 16	ENSP00000364269.1	A0A075B6H3
	TMCO4	ENST00000866952.1		c.1552G>T	p.Val518Leu	missense	Exon 18 of 18	ENSP00000537011.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461312 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726966

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0047	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.82	L
PhyloP100		7.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.010	D
Sift4G	Benign	0.18	T
Polyphen		0.86	P
Vest4		0.77
MutPred		0.70		Loss of ubiquitination at K516 (P = 0.0609)
MVP		0.15
MPC		0.40
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.35
gMVP		0.59
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs754745907; hg19: chr1-20009886; COSMIC: COSV53872336; COSMIC: COSV53872336;