6-13634448-T-A

Variant names:

• chr6-13634448-T-A
• rs751214595
• NM_005493.3:c.1778A>T

Variant summary

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

The NM_005493.3(RANBP9):​c.1778A>T​(p.Asp593Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D593A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RANBP9 NM_005493.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67
• 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.1778A>T	p.Asp593Val	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.1778A>T	p.Asp593Val	missense	Exon 11 of 14	ENSP00000011619.3	Q96S59-1
	RANBP9	ENST00000940147.1		c.1778A>T	p.Asp593Val	missense	Exon 11 of 14	ENSP00000610206.1
	RANBP9	ENST00000962251.1		c.1754A>T	p.Asp585Val	missense	Exon 11 of 14	ENSP00000632310.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250960 AF XY: 0.00000737

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.022	D
Sift4G	Benign	0.14	T
Polyphen		0.78	P
Vest4		0.61
MutPred		0.27		Gain of catalytic residue at E592 (P = 0.0708)
MVP		0.51
MPC		0.12
ClinPred		0.57	D
GERP RS		6.0
Varity_R		0.21
gMVP		0.38
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs751214595; hg19: chr6-13634680;