NM_032326.4:c.194A>C

Variant names:

• chr4-950422-A-C
• rs34884217
• NM_032326.4:c.194A>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032326.4(TMEM175):​c.194A>C​(p.Gln65Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0918 in 1,611,220 control chromosomes in the GnomAD database, including 7,834 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 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 Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.068 (516 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7318 hom.)
• Consequence: TMEM175 NM_032326.4 missense, splice_region
• Scores: Splicing: ADA: 0.00001931
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.96

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.614485).
• BP6: Variant 4-950422-A-C is Benign according to our data. Variant chr4-950422-A-C is described in ClinVar as [Benign]. Clinvar id is 1178472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM175	NM_032326.4	c.194A>C	p.Gln65Pro	missense_variant, splice_region_variant	Exon 4 of 11	ENST00000264771.9	NP_115702.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM175	ENST00000264771.9	c.194A>C	p.Gln65Pro	missense_variant, splice_region_variant	Exon 4 of 11	1	NM_032326.4	ENSP00000264771.4

Frequencies

GnomAD3 genomes AF: 0.0679 AC: 10336 AN: 152196 Hom.: 516 Cov.: 32

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0637

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0265

Gnomad FIN AF: 0.0508

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0826

GnomAD3 exomes AF: 0.0703 AC: 17645 AN: 251040 Hom.: 891 AF XY: 0.0714 AC XY: 9684 AN XY: 135698

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.0505

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0297

Gnomad FIN exome AF: 0.0530

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.0808

GnomAD4 exome AF: 0.0943 AC: 137619 AN: 1458906 Hom.: 7318 Cov.: 30 AF XY: 0.0927 AC XY: 67282 AN XY: 726034

Gnomad4 AFR exome AF: 0.0168

Gnomad4 AMR exome AF: 0.0525

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0305

Gnomad4 FIN exome AF: 0.0522

Gnomad4 NFE exome AF: 0.109

Gnomad4 OTH exome AF: 0.0874

GnomAD4 genome AF: 0.0679 AC: 10336 AN: 152314 Hom.: 516 Cov.: 32 AF XY: 0.0644 AC XY: 4797 AN XY: 74484

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.0636

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.0508

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.0818

Alfa AF: 0.0950 Hom.: 971

Bravo AF: 0.0686

TwinsUK AF: 0.101 AC: 376

ALSPAC AF: 0.114 AC: 438

ESP6500AA AF: 0.0229 AC: 101

ESP6500EA AF: 0.107 AC: 921

ExAC AF: 0.0700 AC: 8504

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.107

EpiControl AF: 0.105

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31658403, 30389748) -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.49
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.88
FATHMM_MKL	Uncertain	0.94	D
ClinPred		0.036	T
GERP RS		0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34884217; hg19: chr4-944210;