Variant chr4-950422-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The NM_001297425.2(TMEM175):c.-51-2A>C variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 516 hom., cov: 32)

Exomes 𝑓: 0.094 ( 7318 hom. )

Consequence

TMEM175
NM_001297425.2 splice_acceptor, intron

Scores

Splicing: ADA: 0.00001931

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.96

Variant links:

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]

TMEM175 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07486209 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6, offset of -3, new splice context is: gcagtgctcttgtattccAGccg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

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 link	c.194A>C	p.Gln65Pro	missense_variant, splice_region_variant	Exon 4 of 11	ENST00000264771.9	NP_115702.1	Q9BSA9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM175	ENST00000264771.9 link	c.194A>C	p.Gln65Pro	missense_variant, splice_region_variant	Exon 4 of 11	1	NM_032326.4	ENSP00000264771.4		Q9BSA9-1

Frequencies

GnomAD3 genomes

AF:

0.0679

AC:

10336

AN:

152196

Hom.:

516

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0927

AC XY:

67282

AN XY:

726034

show subpopulations

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.:

AF XY:

0.0644

AC XY:

4797

AN XY:

74484

show subpopulations

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:

AN:

3478

EpiCase

AF:

0.107

EpiControl

AF:

0.105

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 31658403, 30389748) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.49

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.88

FATHMM_MKL

Uncertain

0.94

ClinPred

0.036

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over