chr12-130876170-A-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006325.5(RAN):​c.*244A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000659 in 547,768 control chromosomes in the GnomAD database, including 1 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 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BS2: High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAN	NM_006325.5	c.*244A>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000543796.6	NP_006316.1
RAN	NM_001300796.2	c.*244A>C		3_prime_UTR_variant	Exon 6 of 6		NP_001287725.1
RAN	NM_001300797.2	c.*244A>C		3_prime_UTR_variant	Exon 6 of 6		NP_001287726.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAN	ENST00000543796.6	c.*244A>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_006325.5	ENSP00000446215.1
RAN	ENST00000541679.7	c.*291A>C		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000483687.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000797 AC: 315 AN: 395444 Hom.: 1 Cov.: 2 AF XY: 0.00117 AC XY: 243 AN XY: 208128

African (AFR) AF: 0.00 AC: 0 AN: 11384

American (AMR) AF: 0.00 AC: 0 AN: 14342

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 27534

South Asian (SAS) AF: 0.00732 AC: 291 AN: 39756

European-Finnish (FIN) AF: 0.0000777 AC: 2 AN: 25734

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

European-Non Finnish (NFE) AF: 0.0000626 AC: 15 AN: 239724

Other (OTH) AF: 0.000306 AC: 7 AN: 22868

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00683 AC: 33 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: 0.000191 AC: 13 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000972 Hom.: 2

Bravo AF: 0.0000453

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		1.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2

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;