1-54036672-C-G

Variant names:

• chr1-54036672-C-G
• NM_004872.5:c.754G>C
• TMEM59 p.Val252Leu

Variant summary

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

The NM_004872.5(TMEM59):​c.754G>C​(p.Val252Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V252I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM59 NM_004872.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.20
• Publications: 0 publications found

Genes affected

TMEM59 (HGNC:1239): (transmembrane protein 59) This gene encodes a protein shown to regulate autophagy in response to bacterial infection. This protein may also regulate the retention of amyloid precursor protein (APP) in the Golgi apparatus through its control of APP glycosylation. Overexpression of this protein has been found to promote apoptosis in a glioma cell line. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

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_004872.5. 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
	TMEM59	NM_004872.5	MANE Select	c.754G>C	p.Val252Leu	missense	Exon 7 of 8	NP_004863.2
	TMEM59	NM_001305043.2		c.757G>C	p.Val253Leu	missense	Exon 7 of 8	NP_001291972.1
	TMEM59	NM_001305050.2		c.556G>C	p.Val186Leu	missense	Exon 5 of 6	NP_001291979.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM59	ENST00000234831.10	TSL:1 MANE Select	c.754G>C	p.Val252Leu	missense	Exon 7 of 8	ENSP00000234831.5	Q9BXS4
	TMEM59	ENST00000371348.5	TSL:1	c.361G>C	p.Val121Leu	missense	Exon 6 of 7	ENSP00000360399.1	Q5T6Z8
	TMEM59	ENST00000864587.1		c.874G>C	p.Val292Leu	missense	Exon 8 of 9	ENSP00000534646.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.017	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.69
Mutation Taster		=44/56	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-54502345;