rs2290405

Variant names:

• chr4-953186-G-A
• rs2290405
• NM_032326.4:c.463-4G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-953186-G-A
• chr4-953186-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032326.4(TMEM175):​c.463-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 1,599,454 control chromosomes in the GnomAD database, including 278,547 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.59 (26409 hom., cov: 33)
  • Exomes 𝑓: 0.59 (252138 hom.)
• Consequence: TMEM175 NM_032326.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001806
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• Publications: 26 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM175	NM_032326.4	c.463-4G>A		splice_region_variant, intron_variant	Intron 7 of 10	ENST00000264771.9	NP_115702.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM175	ENST00000264771.9	c.463-4G>A		splice_region_variant, intron_variant	Intron 7 of 10	1	NM_032326.4	ENSP00000264771.4

Frequencies

GnomAD3 genomes AF: 0.586 AC: 89018 AN: 151948 Hom.: 26385 Cov.: 33

Gnomad AFR AF: 0.626

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.594

GnomAD2 exomes AF: 0.563 AC: 136129 AN: 241794 AF XY: 0.572

Gnomad AFR exome AF: 0.622

Gnomad AMR exome AF: 0.411

Gnomad ASJ exome AF: 0.594

Gnomad EAS exome AF: 0.525

Gnomad FIN exome AF: 0.521

Gnomad NFE exome AF: 0.596

Gnomad OTH exome AF: 0.570

GnomAD4 exome AF: 0.588 AC: 851449 AN: 1447388 Hom.: 252138 Cov.: 50 AF XY: 0.590 AC XY: 423979 AN XY: 718402

African (AFR) AF: 0.625 AC: 20747 AN: 33210

American (AMR) AF: 0.423 AC: 18391 AN: 43494

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 15102 AN: 25362

East Asian (EAS) AF: 0.491 AC: 19364 AN: 39410

South Asian (SAS) AF: 0.622 AC: 52704 AN: 84798

European-Finnish (FIN) AF: 0.523 AC: 27428 AN: 52478

Middle Eastern (MID) AF: 0.653 AC: 3723 AN: 5704

European-Non Finnish (NFE) AF: 0.597 AC: 658966 AN: 1103252

Other (OTH) AF: 0.587 AC: 35024 AN: 59680

GnomAD4 genome AF: 0.586 AC: 89082 AN: 152066 Hom.: 26409 Cov.: 33 AF XY: 0.579 AC XY: 43059 AN XY: 74314

African (AFR) AF: 0.626 AC: 25939 AN: 41462

American (AMR) AF: 0.497 AC: 7592 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2065 AN: 3472

East Asian (EAS) AF: 0.508 AC: 2621 AN: 5158

South Asian (SAS) AF: 0.624 AC: 3008 AN: 4822

European-Finnish (FIN) AF: 0.519 AC: 5485 AN: 10574

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.594 AC: 40403 AN: 67976

Other (OTH) AF: 0.598 AC: 1262 AN: 2112

Alfa AF: 0.593 Hom.: 58276

Bravo AF: 0.586

Asia WGS AF: 0.580 AC: 2022 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.24
DANN	Benign	0.52
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0040
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: rs2290405; hg19: chr4-946974; COSMIC: COSV53278973; COSMIC: COSV53278973;