chr4-950422-A-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

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

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: Benign. The variant received -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	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

GnomAD2 exomes AF: 0.0703 AC: 17645 AN: 251040 AF XY: 0.0714

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 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 AC: 563 AN: 33454

Gnomad4 AMR exome AF: 0.0525 AC: 2346 AN: 44682

Gnomad4 ASJ exome AF: 0.111 AC: 2909 AN: 26112

Gnomad4 EAS exome AF: 0.000302 AC: 12 AN: 39688

Gnomad4 SAS exome AF: 0.0305 AC: 2633 AN: 86216

Gnomad4 FIN exome AF: 0.0522 AC: 2788 AN: 53378

Gnomad4 NFE exome AF: 0.109 AC: 120652 AN: 1109340

Gnomad4 Remaining exome AF: 0.0874 AC: 5269 AN: 60278

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 AC: 0.0200356 AN: 0.0200356

Gnomad4 AMR AF: 0.0636 AC: 0.0635948 AN: 0.0635948

Gnomad4 ASJ AF: 0.108 AC: 0.107719 AN: 0.107719

Gnomad4 EAS AF: 0.000386 AC: 0.000385802 AN: 0.000385802

Gnomad4 SAS AF: 0.0269 AC: 0.0269374 AN: 0.0269374

Gnomad4 FIN AF: 0.0508 AC: 0.0507724 AN: 0.0507724

Gnomad4 NFE AF: 0.106 AC: 0.106413 AN: 0.106413

Gnomad4 OTH AF: 0.0818 AC: 0.081758 AN: 0.081758

Alfa AF: 0.0904 Hom.: 1425

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
Varity_R		0.57
Mutation Taster		=58/42	polymorphism (auto)

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; COSMIC: COSV107288423; COSMIC: COSV107288423;