rs34311866

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032326.4(TMEM175):c.1178T>C(p.Met393Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,603,214 control chromosomes in the GnomAD database, including 29,080 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 2053 hom., cov: 34)

Exomes 𝑓: 0.19 ( 27027 hom. )

Consequence

TMEM175
NM_032326.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.29

Publications

128 publications found

Variant links:

Genes affected

TMEM175 (HGNC:28709): (transmembrane protein 175) Enables potassium ion leak channel activity. Involved in potassium ion transmembrane transport. Located in endosome and lysosome. Is integral component of endosome membrane and integral component of lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM175 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023782551).

BP6

Variant 4-958159-T-C is Benign according to our data. Variant chr4-958159-T-C is described in ClinVar as Benign. ClinVar VariationId is 1246424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032326.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM175	NM_032326.4	MANE Select	c.1178T>C	p.Met393Thr	missense	Exon 11 of 11	NP_115702.1
TMEM175	NM_001297423.2		c.932T>C	p.Met311Thr	missense	Exon 11 of 11	NP_001284352.1
TMEM175	NM_001297424.2		c.932T>C	p.Met311Thr	missense	Exon 9 of 9	NP_001284353.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM175	ENST00000264771.9	TSL:1 MANE Select	c.1178T>C	p.Met393Thr	missense	Exon 11 of 11	ENSP00000264771.4
TMEM175	ENST00000622959.3	TSL:1	c.830T>C	p.Met277Thr	missense	Exon 12 of 12	ENSP00000485461.1
TMEM175	ENST00000513952.5	TSL:1	n.*1200T>C		non_coding_transcript_exon	Exon 12 of 12	ENSP00000427218.1

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21549

AN:

152150

Hom.:

2055

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0316

Gnomad AMI

AF:

0.232

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.300

Gnomad EAS

AF:

0.138

Gnomad SAS

AF:

0.320

Gnomad FIN

AF:

0.202

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.186

Gnomad OTH

AF:

0.141

GnomAD2 exomes

AF:

0.180

AC:

43259

AN:

240964

AF XY:

0.194

show subpopulations

Gnomad AFR exome

AF:

0.0294

Gnomad AMR exome

AF:

0.0718

Gnomad ASJ exome

AF:

0.295

Gnomad EAS exome

AF:

0.128

Gnomad FIN exome

AF:

0.193

Gnomad NFE exome

AF:

0.190

Gnomad OTH exome

AF:

0.185

GnomAD4 exome

AF:

0.185

AC:

268511

AN:

1450946

Hom.:

27027

Cov.:

AF XY:

0.191

AC XY:

137971

AN XY:

722146

show subpopulations

African (AFR)

AF:

0.0277

AC:

926

AN:

33468

American (AMR)

AF:

0.0751

AC:

3357

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

7952

AN:

26092

East Asian (EAS)

AF:

0.151

AC:

6000

AN:

39652

South Asian (SAS)

AF:

0.328

AC:

28223

AN:

86166

European-Finnish (FIN)

AF:

0.202

AC:

8807

AN:

43498

Middle Eastern (MID)

AF:

0.211

AC:

1216

AN:

5758

European-Non Finnish (NFE)

AF:

0.181

AC:

200852

AN:

1111356

Other (OTH)

AF:

0.185

AC:

11178

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

15804

31608

47413

63217

79021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6984

13968

20952

27936

34920

<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:

0.141

AC:

21543

AN:

152268

Hom.:

2053

Cov.:

AF XY:

0.144

AC XY:

10707

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0315

AC:

1312

AN:

41588

American (AMR)

AF:

0.102

AC:

1564

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

1041

AN:

3470

East Asian (EAS)

AF:

0.138

AC:

714

AN:

5174

South Asian (SAS)

AF:

0.320

AC:

1546

AN:

4828

European-Finnish (FIN)

AF:

0.202

AC:

2143

AN:

10606

Middle Eastern (MID)

AF:

0.187

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.186

AC:

12662

AN:

67978

Other (OTH)

AF:

0.140

AC:

295

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

999

1999

2998

3998

4997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

262

524

786

1048

1310

<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:

0.240

Hom.:

5618

Bravo

AF:

0.122

TwinsUK

AF:

0.180

AC:

667

ALSPAC

AF:

0.173

AC:

667

ESP6500AA

AF:

0.0355

AC:

156

ESP6500EA

AF:

0.190

AC:

1629

ExAC

AF:

0.181

AC:

21957

Asia WGS

AF:

0.227

AC:

787

AN:

3478

EpiCase

AF:

0.185

EpiControl

AF:

0.195

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Apr 19, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31658403, 31261387, 30389748)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

9.5

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.015

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.59

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

1.3

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.8

REVEL

Benign

0.15

Sift

Benign

0.032

Sift4G

Uncertain

0.0030

Polyphen

0.0

Vest4

0.038

MPC

0.18

ClinPred

0.0029

GERP RS

0.79

Varity_R

0.22

gMVP

0.75

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over