rs34311866

chr4-958159-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (2053 hom., cov: 34)
  • Exomes 𝑓: 0.19 (27027 hom.)
• Consequence: TMEM175 NM_032326.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.29

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 1246424.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM175	NM_032326.4	c.1178T>C	p.Met393Thr	missense_variant	11/11	ENST00000264771.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM175	ENST00000264771.9	c.1178T>C	p.Met393Thr	missense_variant	11/11	1	NM_032326.4	P1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21549 AN: 152150 Hom.: 2055 Cov.: 34

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

GnomAD3 exomes AF: 0.180 AC: 43259 AN: 240964 Hom.: 4867 AF XY: 0.194 AC XY: 25497 AN XY: 131664

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 SAS exome AF: 0.327

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.: 33 AF XY: 0.191 AC XY: 137971 AN XY: 722146

Gnomad4 AFR exome AF: 0.0277

Gnomad4 AMR exome AF: 0.0751

Gnomad4 ASJ exome AF: 0.305

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.181

Gnomad4 OTH exome AF: 0.185

GnomAD4 genome AF: 0.141 AC: 21543 AN: 152268 Hom.: 2053 Cov.: 34 AF XY: 0.144 AC XY: 10707 AN XY: 74460

Gnomad4 AFR AF: 0.0315

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.300

Gnomad4 EAS AF: 0.138

Gnomad4 SAS AF: 0.320

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.186

Gnomad4 OTH AF: 0.140

Alfa AF: 0.264 Hom.: 5279

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 19, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	9.5
Dann	Benign	0.45
DEOGEN2	Benign	0.015	T;.;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.59	T;.;T;T
MetaRNN	Benign	0.024	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N;N;N;.
REVEL	Benign	0.15
Sift	Benign	0.032	D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.0	B;.;B;.
Vest4		0.038
MPC		0.18
ClinPred		0.0029	T
GERP RS		0.79
Varity_R		0.22
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs34311866; hg19: chr4-951947; COSMIC: COSV53281326; COSMIC: COSV53281326;