chr1-54032182-T-C

Variant names:

• chr1-54032182-T-C
• rs759133703
• NM_004872.5:c.940A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004872.5(TMEM59):​c.940A>G​(p.Thr314Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T314S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM59 NM_004872.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.119
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.121985525).

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.940A>G	p.Thr314Ala	missense	Exon 8 of 8	NP_004863.2
	TMEM59	NM_001305043.2		c.943A>G	p.Thr315Ala	missense	Exon 8 of 8	NP_001291972.1
	TMEM59	NM_001305050.2		c.742A>G	p.Thr248Ala	missense	Exon 6 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.940A>G	p.Thr314Ala	missense	Exon 8 of 8	ENSP00000234831.5	Q9BXS4
	TMEM59	ENST00000371348.5	TSL:1	c.547A>G	p.Thr183Ala	missense	Exon 7 of 7	ENSP00000360399.1	Q5T6Z8
	TMEM59	ENST00000864587.1		c.1060A>G	p.Thr354Ala	missense	Exon 9 of 9	ENSP00000534646.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249920 AF XY: 0.00000740

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459312 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 725998

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110800

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.12
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.049
Sift	Benign	0.34	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.045
MutPred		0.17		Loss of glycosylation at T314 (P = 0.0159)
MVP		0.23
MPC		0.15
ClinPred		0.034	T
GERP RS		0.086
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.29
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs759133703; hg19: chr1-54497855;