chr4-958159-T-C

Variant names:

• chr4-958159-T-C
• rs34311866
• NM_032326.4:c.1178T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.29
• Publications: 128 publications found

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM175	NM_032326.4	MANE Select	c.1178T>C	p.Met393Thr	missense	Exon 11 of 11	NP_115702.1	Q9BSA9-1
	TMEM175	NM_001297423.2		c.932T>C	p.Met311Thr	missense	Exon 11 of 11	NP_001284352.1	F6UWG6
	TMEM175	NM_001297424.2		c.932T>C	p.Met311Thr	missense	Exon 9 of 9	NP_001284353.1	F6UWG6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM175	ENST00000264771.9	TSL:1 MANE Select	c.1178T>C	p.Met393Thr	missense	Exon 11 of 11	ENSP00000264771.4	Q9BSA9-1
	TMEM175	ENST00000622959.3	TSL:1	c.830T>C	p.Met277Thr	missense	Exon 12 of 12	ENSP00000485461.1	Q9BSA9-2
	TMEM175	ENST00000513952.5	TSL:1	n.*1200T>C		non_coding_transcript_exon	Exon 12 of 12	ENSP00000427218.1	D6RCD9

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

GnomAD2 exomes AF: 0.180 AC: 43259 AN: 240964 AF XY: 0.194

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

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

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

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: 55 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12662 AN: 67978

Other (OTH) AF: 0.140 AC: 295 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.15
Sift	Benign	0.032	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.0	B
Vest4		0.038
MPC		0.18
ClinPred		0.0029	T
GERP RS		0.79
Varity_R		0.22
gMVP		0.75
Mutation Taster		=91/9	polymorphism (auto)

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

Other links and lift over

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