chr4-950422-A-T

Variant names:

• chr4-950422-A-T
• rs34884217
• ENST00000622959.3:c.-191A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001297423.2(TMEM175):​c.-53A>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000685 in 1,459,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM175 NM_001297423.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.000009458
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.121).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001297423.2. 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.194A>T	p.Gln65Leu	missense splice_region	Exon 4 of 11	NP_115702.1	Q9BSA9-1
	TMEM175	NM_001297423.2		c.-53A>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 11	NP_001284352.1	F6UWG6
	TMEM175	NM_001297424.2		c.-53A>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001284353.1	F6UWG6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM175	ENST00000622959.3	TSL:1	c.-191A>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 12	ENSP00000485461.1	Q9BSA9-2
	TMEM175	ENST00000264771.9	TSL:1 MANE Select	c.194A>T	p.Gln65Leu	missense splice_region	Exon 4 of 11	ENSP00000264771.4	Q9BSA9-1
	TMEM175	ENST00000622959.3	TSL:1	c.-191A>T		splice_region	Exon 5 of 12	ENSP00000485461.1	Q9BSA9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459882 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726434

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110268

Other (OTH) AF: 0.00 AC: 0 AN: 60302

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.48
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.76
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.0097	T
PhyloP100		4.0
ClinPred		0.62	D
GERP RS		0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000095
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs34884217; hg19: chr4-944210;