NM_005493.3:c.1681G>A

Variant names:

• chr6-13634545-C-T
• rs1335566081
• NM_005493.3:c.1681G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005493.3(RANBP9):​c.1681G>A​(p.Val561Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,447,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RANBP9 NM_005493.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80
• Publications: 0 publications found

Genes affected

RANBP9 (HGNC:13727): (RAN binding protein 9) This gene encodes a protein that binds RAN, 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 protein encoded by this gene has also been shown to interact with several other proteins, including met proto-oncogene, homeodomain interacting protein kinase 2, androgen receptor, and cyclin-dependent kinase 11. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005493.3. 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
	RANBP9	NM_005493.3	MANE Select	c.1681G>A	p.Val561Ile	missense	Exon 11 of 14	NP_005484.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP9	ENST00000011619.6	TSL:1 MANE Select	c.1681G>A	p.Val561Ile	missense	Exon 11 of 14	ENSP00000011619.3	Q96S59-1
	RANBP9	ENST00000940147.1		c.1681G>A	p.Val561Ile	missense	Exon 11 of 14	ENSP00000610206.1
	RANBP9	ENST00000962251.1		c.1657G>A	p.Val553Ile	missense	Exon 11 of 14	ENSP00000632310.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 241584 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447718 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718962

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32842

American (AMR) AF: 0.00 AC: 0 AN: 42160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25644

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 83832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105228

Other (OTH) AF: 0.0000167 AC: 1 AN: 59846

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.067	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.39
Sift	Benign	0.037	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.64
MutPred		0.31		Loss of loop (P = 0.0804)
MVP		0.54
MPC		0.25
ClinPred		0.79	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.17
Mutation Taster		=61/39	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: rs1335566081; hg19: chr6-13634777;