Genetic Variant RAN:c.*244A>G (chr12-130876170-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.16

Variant links:

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]

RAN links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 276 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RAN	NM_006325.5 link	c.*244A>G	3_prime_UTR_variant	Exon 7 of 7	ENST00000543796.6	NP_006316.1	P62826
RAN	NM_001300796.2 link	c.*244A>G	3_prime_UTR_variant	Exon 6 of 6		NP_001287725.1	P62826B4DV51
RAN	NM_001300797.2 link	c.*244A>G	3_prime_UTR_variant	Exon 6 of 6		NP_001287726.1	P62826B4DV51

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAN	ENST00000543796.6 link	c.*244A>G		3_prime_UTR_variant	Exon 7 of 7	1	NM_006325.5	ENSP00000446215.1		P62826
RAN	ENST00000541679.7 link	c.*291A>G		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000483687.1		A0A087X0W0

Frequencies

GnomAD3 genomes

AF:

0.00180

AC:

274

AN:

152206

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00209

AC XY:

436

AN XY:

208126

show subpopulations

Gnomad4 AFR exome

AF:

0.000176

Gnomad4 AMR exome

AF:

0.000279

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0223

Gnomad4 SAS exome

AF:

0.00194

Gnomad4 FIN exome

AF:

0.0000389

Gnomad4 NFE exome

AF:

0.000229

Gnomad4 OTH exome

AF:

0.00254

GnomAD4 genome

AF:

0.00181

AC:

276

AN:

152324

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0423

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000330

Hom.:

Bravo

AF:

0.00222

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.83

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over