12-130876170-A-G

Variant names:

• chr12-130876170-A-G
• rs3803012
• NM_006325.5:c.*244A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006325.5(RAN):​c.*244A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 547,760 control chromosomes in the GnomAD database, including 23 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 0.0018 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (17 hom.)
• Consequence: RAN NM_006325.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00181 (276/152324) while in subpopulation EAS AF = 0.0423 (219/5178). AF 95% confidence interval is 0.0377. There are 6 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 276 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006325.5. 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
	RAN	NM_006325.5	MANE Select	c.*244A>G		3_prime_UTR	Exon 7 of 7	NP_006316.1	P62826
	RAN	NM_001300796.2		c.*244A>G		3_prime_UTR	Exon 6 of 6	NP_001287725.1	B4DV51
	RAN	NM_001300797.2		c.*244A>G		3_prime_UTR	Exon 6 of 6	NP_001287726.1	B4DV51

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAN	ENST00000543796.6	TSL:1 MANE Select	c.*244A>G		3_prime_UTR	Exon 7 of 7	ENSP00000446215.1	P62826
	RAN	ENST00000392369.6	TSL:1	c.*244A>G		3_prime_UTR	Exon 6 of 6	ENSP00000376176.2	P62826
	RAN	ENST00000541679.7	TSL:5	c.*291A>G		3_prime_UTR	Exon 4 of 4	ENSP00000483687.1	A0A087X0W0

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 152206 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0418

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00205 AC: 811 AN: 395436 Hom.: 17 Cov.: 2 AF XY: 0.00209 AC XY: 436 AN XY: 208126

African (AFR) AF: 0.000176 AC: 2 AN: 11384

American (AMR) AF: 0.000279 AC: 4 AN: 14342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12348

East Asian (EAS) AF: 0.0223 AC: 614 AN: 27530

South Asian (SAS) AF: 0.00194 AC: 77 AN: 39752

European-Finnish (FIN) AF: 0.0000389 AC: 1 AN: 25734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1754

European-Non Finnish (NFE) AF: 0.000229 AC: 55 AN: 239724

Other (OTH) AF: 0.00254 AC: 58 AN: 22868

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152324 Hom.: 6 Cov.: 33 AF XY: 0.00199 AC XY: 148 AN XY: 74496

African (AFR) AF: 0.000553 AC: 23 AN: 41582

American (AMR) AF: 0.000392 AC: 6 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0423 AC: 219 AN: 5178

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000343 Hom.: 2

Bravo AF: 0.00222

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.83
PhyloP100		1.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs3803012; hg19: chr12-131360715;