rs14035

chr12-130876696-C-T

Variant summary

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

The NM_006325.5(RAN):c.*770C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 152,024 control chromosomes in the GnomAD database, including 7,907 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.32 (7907 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: RAN NM_006325.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.147

Genes affected

RAN (HGNC:9846): (RAN, member RAS oncogene family) RAN (ras-related nuclear protein) is a small GTP binding protein belonging to the RAS superfamily that is essential for the translocation of RNA and proteins through the nuclear pore complex. The RAN protein is also involved in control of DNA synthesis and cell cycle progression. Nuclear localization of RAN requires the presence of regulator of chromosome condensation 1 (RCC1). Mutations in RAN disrupt DNA synthesis. Because of its many functions, it is likely that RAN interacts with several other proteins. RAN regulates formation and organization of the microtubule network independently of its role in the nucleus-cytosol exchange of macromolecules. RAN could be a key signaling molecule regulating microtubule polymerization during mitosis. RCC1 generates a high local concentration of RAN-GTP around chromatin which, in turn, induces the local nucleation of microtubules. RAN is an androgen receptor (AR) coactivator that binds differentially with different lengths of polyglutamine within the androgen receptor. Polyglutamine repeat expansion in the AR is linked to Kennedy's disease (X-linked spinal and bulbar muscular atrophy). RAN coactivation of the AR diminishes with polyglutamine expansion within the AR, and this weak coactivation may lead to partial androgen insensitivity during the development of Kennedy's disease. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAN	NM_006325.5	c.*770C>T		3_prime_UTR_variant	7/7	ENST00000543796.6
RAN	NM_001300796.2	c.*770C>T		3_prime_UTR_variant	6/6
RAN	NM_001300797.2	c.*770C>T		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAN	ENST00000543796.6	c.*770C>T		3_prime_UTR_variant	7/7	1	NM_006325.5	P1
RAN	ENST00000448750.7	c.*770C>T		3_prime_UTR_variant	6/6	2
RAN	ENST00000541630.5	c.*770C>T		3_prime_UTR_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49084 AN: 151906 Hom.: 7895 Cov.: 33

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.317

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.323 AC: 49123 AN: 152024 Hom.: 7907 Cov.: 33 AF XY: 0.323 AC XY: 24012 AN XY: 74306

Gnomad4 AFR AF: 0.355

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.338

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.389

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.315

Alfa AF: 0.316 Hom.: 9714

Bravo AF: 0.319

Asia WGS AF: 0.204 AC: 711 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.7
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs14035; hg19: chr12-131361241;