Genetic Variant TMEM59:p.Val252Ile (chr1-54036672-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004872.5(TMEM59):c.754G>A(p.Val252Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000379 in 1,610,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. V252L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

TMEM59
NM_004872.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.20

Publications

1 publications found

Variant links:

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]

TMEM59 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.090630084).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM59	NM_004872.5	MANE Select	c.754G>A	p.Val252Ile	missense	Exon 7 of 8	NP_004863.2
TMEM59	NM_001305043.2		c.757G>A	p.Val253Ile	missense	Exon 7 of 8	NP_001291972.1
TMEM59	NM_001305050.2		c.556G>A	p.Val186Ile	missense	Exon 5 of 6	NP_001291979.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM59	ENST00000234831.10	TSL:1 MANE Select	c.754G>A	p.Val252Ile	missense	Exon 7 of 8	ENSP00000234831.5	Q9BXS4
TMEM59	ENST00000371348.5	TSL:1	c.361G>A	p.Val121Ile	missense	Exon 6 of 7	ENSP00000360399.1	Q5T6Z8
TMEM59	ENST00000864587.1		c.874G>A	p.Val292Ile	missense	Exon 8 of 9	ENSP00000534646.1

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151684

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000924

AC:

AN:

248796

AF XY:

0.0000892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00115

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000391

AC:

AN:

1459226

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

725910

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33362

American (AMR)

AF:

0.0000225

AC:

AN:

44504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26036

East Asian (EAS)

AF:

0.000935

AC:

AN:

39566

South Asian (SAS)

AF:

0.00

AC:

AN:

85832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110582

Other (OTH)

AF:

0.000299

AC:

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151684

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74044

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41250

American (AMR)

AF:

0.00

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000773

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67962

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.019

MetaRNN

Benign

0.091

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.9

PhyloP100

7.2

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.63

REVEL

Benign

0.18

Sift

Uncertain

0.010

Sift4G

Benign

0.078

Polyphen

1.0

Vest4

0.73

MutPred

0.37

Loss of catalytic residue at V252 (P = 0.1589)

MVP

0.63

MPC

0.61

ClinPred

0.22

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.51

Mutation Taster

=50/50

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over