rs2290405

Positions:

• chr4-953186-G-A
• chr4-953186-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032326.4(TMEM175):​c.463-4G>A variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001806
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82

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 -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/exons	MANE	UniProt
TMEM175	NM_032326.4	c.463-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000264771.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM175	ENST00000264771.9	c.463-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_032326.4	P1

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

GnomAD3 exomes AF: 0.563 AC: 136129 AN: 241794 Hom.: 39063 AF XY: 0.572 AC XY: 74655 AN XY: 130626

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 SAS exome AF: 0.621

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

Gnomad4 AFR exome AF: 0.625

Gnomad4 AMR exome AF: 0.423

Gnomad4 ASJ exome AF: 0.595

Gnomad4 EAS exome AF: 0.491

Gnomad4 SAS exome AF: 0.622

Gnomad4 FIN exome AF: 0.523

Gnomad4 NFE exome AF: 0.597

Gnomad4 OTH exome AF: 0.587

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

Gnomad4 AFR AF: 0.626

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.595

Gnomad4 EAS AF: 0.508

Gnomad4 SAS AF: 0.624

Gnomad4 FIN AF: 0.519

Gnomad4 NFE AF: 0.594

Gnomad4 OTH AF: 0.598

Alfa AF: 0.594 Hom.: 43679

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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs2290405; hg19: chr4-946974; COSMIC: COSV53278973; COSMIC: COSV53278973;