chr4-953305-C-A

Variant names:

• chr4-953305-C-A
• rs201589218
• NM_032326.4:c.578C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032326.4(TMEM175):​c.578C>A​(p.Pro193Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P193L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM175 NM_032326.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.87
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799

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.578C>A	p.Pro193Gln	missense	Exon 8 of 11	NP_115702.1	Q9BSA9-1
	TMEM175	NM_001297423.2		c.332C>A	p.Pro111Gln	missense	Exon 8 of 11	NP_001284352.1	F6UWG6
	TMEM175	NM_001297424.2		c.332C>A	p.Pro111Gln	missense	Exon 6 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.578C>A	p.Pro193Gln	missense	Exon 8 of 11	ENSP00000264771.4	Q9BSA9-1
	TMEM175	ENST00000622959.3	TSL:1	c.230C>A	p.Pro77Gln	missense	Exon 9 of 12	ENSP00000485461.1	Q9BSA9-2
	TMEM175	ENST00000513952.5	TSL:1	n.*600C>A		non_coding_transcript_exon	Exon 9 of 12	ENSP00000427218.1	D6RCD9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461628 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111892

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.9
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.28
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.60		Gain of catalytic residue at P193 (P = 0.0133)
MVP		0.30
MPC		0.54
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.33
gMVP		0.86
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs201589218; hg19: chr4-947093;