4-947788-T-G

Variant names:

• chr4-947788-T-G
• rs1728365808
• NM_032326.4:c.49T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032326.4(TMEM175):​c.49T>G​(p.Cys17Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: TMEM175 NM_032326.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.46
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045628995).

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.49T>G	p.Cys17Gly	missense	Exon 2 of 11	NP_115702.1	Q9BSA9-1
	TMEM175	NM_001297423.2		c.-659T>G		5_prime_UTR	Exon 2 of 11	NP_001284352.1	F6UWG6
	TMEM175	NM_001297426.2		c.-541T>G		5_prime_UTR	Exon 2 of 12	NP_001284355.1	Q9BSA9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM175	ENST00000264771.9	TSL:1 MANE Select	c.49T>G	p.Cys17Gly	missense	Exon 2 of 11	ENSP00000264771.4	Q9BSA9-1
	TMEM175	ENST00000622959.3	TSL:1	c.-541T>G		5_prime_UTR	Exon 2 of 12	ENSP00000485461.1	Q9BSA9-2
	TMEM175	ENST00000513952.5	TSL:1	n.49T>G		non_coding_transcript_exon	Exon 2 of 12	ENSP00000427218.1	D6RCD9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460592 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726618

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

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52316

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

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

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	0.056
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.16
DANN	Benign	0.68
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		-2.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.039
Sift	Benign	0.52	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.074
MutPred		0.26		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.014
MPC		0.20
ClinPred		0.039	T
GERP RS		0.28
Varity_R		0.059
gMVP		0.42
Mutation Taster		=97/3	polymorphism

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: rs1728365808; hg19: chr4-941576;