rs1440554721

Variant names:

• chr5-170878097-A-C
• rs1440554721
• NM_022897.5:c.19A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-170878097-A-C
• chr5-170878097-A-G
• chr5-170878097-A-T

Variant summary

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

The NM_022897.5(RANBP17):​c.19A>C​(p.Ser7Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000719 in 1,390,132 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S7G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: RANBP17 NM_022897.5 missense, splice_region
• Scores: Splicing: ADA: 0.1710
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.60
• Publications: 0 publications found

Genes affected

RANBP17 (HGNC:14428): (RAN binding protein 17) The transport of protein and large RNAs through the nuclear pore complexes (NPC) is an energy-dependent and regulated process. The import of proteins with a nuclear localization signal (NLS) is accomplished by recognition of one or more clusters of basic amino acids by the importin-alpha/beta complex; see MIM 600685 and MIM 602738. The small GTPase RAN (MIM 601179) plays a key role in NLS-dependent protein import. RAN-binding protein-17 is a member of the importin-beta superfamily of nuclear transport receptors.[supplied by OMIM, Jul 2002]

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_022897.5. 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
	RANBP17	NM_022897.5	MANE Select	c.19A>C	p.Ser7Arg	missense splice_region	Exon 2 of 28	NP_075048.1	Q546R4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RANBP17	ENST00000523189.6	TSL:1 MANE Select	c.19A>C	p.Ser7Arg	missense splice_region	Exon 2 of 28	ENSP00000427975.1	Q9H2T7-1
	RANBP17	ENST00000519130.5	TSL:1	n.30A>C		splice_region non_coding_transcript_exon	Exon 2 of 6
	RANBP17	ENST00000961946.1		c.19A>C	p.Ser7Arg	missense splice_region	Exon 2 of 29	ENSP00000632005.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1390132 Hom.: 0 Cov.: 29 AF XY: 0.00000146 AC XY: 1 AN XY: 686716

⚠️ 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: 30716

American (AMR) AF: 0.00 AC: 0 AN: 32084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23612

East Asian (EAS) AF: 0.00 AC: 0 AN: 38336

South Asian (SAS) AF: 0.00 AC: 0 AN: 72488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5422

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078210

Other (OTH) AF: 0.00 AC: 0 AN: 57136

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	0.0073	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.097
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.31	T
Polyphen		0.91	P
Vest4		0.70
MutPred		0.39		Loss of disorder (P = 0.0865)
MVP		0.40
MPC		0.035
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.25
gMVP		0.23
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.17
dbscSNV1_RF	Benign	0.47
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: rs1440554721; hg19: chr5-170305101;