rs34884217

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-950422-A-C
• chr4-950422-A-T

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
• Publications: 44 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: 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001297425.2. 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>C	p.Gln65Pro	missense splice_region	Exon 4 of 11	NP_115702.1	Q9BSA9-1
	TMEM175	NM_001297423.2		c.-53A>C		splice_region	Exon 4 of 11	NP_001284352.1	F6UWG6
	TMEM175	NM_001297424.2		c.-53A>C		splice_region	Exon 2 of 9	NP_001284353.1	F6UWG6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM175	ENST00000264771.9	TSL:1 MANE Select	c.194A>C	p.Gln65Pro	missense splice_region	Exon 4 of 11	ENSP00000264771.4	Q9BSA9-1
	TMEM175	ENST00000622959.3	TSL:1	c.-191A>C		splice_region	Exon 5 of 12	ENSP00000485461.1	Q9BSA9-2
	TMEM175	ENST00000622959.3	TSL:1	c.-191A>C		5_prime_UTR	Exon 5 of 12	ENSP00000485461.1	Q9BSA9-2

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

African (AFR) AF: 0.0168 AC: 563 AN: 33454

American (AMR) AF: 0.0525 AC: 2346 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2909 AN: 26112

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39688

South Asian (SAS) AF: 0.0305 AC: 2633 AN: 86216

European-Finnish (FIN) AF: 0.0522 AC: 2788 AN: 53378

Middle Eastern (MID) AF: 0.0776 AC: 447 AN: 5758

European-Non Finnish (NFE) AF: 0.109 AC: 120652 AN: 1109340

Other (OTH) 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

African (AFR) AF: 0.0200 AC: 833 AN: 41576

American (AMR) AF: 0.0636 AC: 973 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0269 AC: 130 AN: 4826

European-Finnish (FIN) AF: 0.0508 AC: 539 AN: 10616

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7238 AN: 68018

Other (OTH) AF: 0.0818 AC: 173 AN: 2116

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.0
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

Other links and lift over

dbSNP: rs34884217; hg19: chr4-944210; COSMIC: COSV107288423; COSMIC: COSV107288423;