chr4-953191-C-T

Variant names:

• chr4-953191-C-T
• rs770466843
• NM_032326.4:c.464C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032326.4(TMEM175):​c.464C>T​(p.Ala155Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,452,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: TMEM175 NM_032326.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002720
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06676).

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.464C>T	p.Ala155Val	missense splice_region	Exon 8 of 11	NP_115702.1	Q9BSA9-1
	TMEM175	NM_001297423.2		c.218C>T	p.Ala73Val	missense splice_region	Exon 8 of 11	NP_001284352.1	F6UWG6
	TMEM175	NM_001297424.2		c.218C>T	p.Ala73Val	missense splice_region	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.464C>T	p.Ala155Val	missense splice_region	Exon 8 of 11	ENSP00000264771.4	Q9BSA9-1
	TMEM175	ENST00000622959.3	TSL:1	c.116C>T	p.Ala39Val	missense splice_region	Exon 9 of 12	ENSP00000485461.1	Q9BSA9-2
	TMEM175	ENST00000513952.5	TSL:1	n.*486C>T		splice_region non_coding_transcript_exon	Exon 9 of 12	ENSP00000427218.1	D6RCD9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000409 AC: 10 AN: 244510 AF XY: 0.0000530

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000207 AC: 30 AN: 1452488 Hom.: 0 Cov.: 33 AF XY: 0.0000222 AC XY: 16 AN XY: 721574

African (AFR) AF: 0.00 AC: 0 AN: 33300

American (AMR) AF: 0.00 AC: 0 AN: 43916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25564

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.000328 AC: 28 AN: 85308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106378

Other (OTH) AF: 0.0000167 AC: 1 AN: 59926

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.21
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	0.31	T
Polyphen		0.0020	B
Vest4		0.34
MutPred		0.31		Gain of sheet (P = 0.0477)
MVP		0.076
MPC		0.16
ClinPred		0.060	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.081
gMVP		0.51
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.020
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: rs770466843; hg19: chr4-946979;