5-170909718-A-T

Position:

• chr5-170909718-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_022897.5(RANBP17):​c.547A>T​(p.Thr183Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000881 in 1,597,752 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00047 (7 hom.)
• Consequence: RANBP17 NM_022897.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.40

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047468245).
• BP6: Variant 5-170909718-A-T is Benign according to our data. Variant chr5-170909718-A-T is described in ClinVar as [Benign]. Clinvar id is 3049366.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00478 (722/150990) while in subpopulation AFR AF= 0.0169 (700/41316). AF 95% confidence interval is 0.0159. There are 4 homozygotes in gnomad4. There are 327 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP17	NM_022897.5	c.547A>T	p.Thr183Ser	missense_variant	6/28	ENST00000523189.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP17	ENST00000523189.6	c.547A>T	p.Thr183Ser	missense_variant	6/28	1	NM_022897.5	P1

Frequencies

GnomAD3 genomes AF: 0.00479 AC: 722 AN: 150876 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000866

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000888

Gnomad OTH AF: 0.000967

GnomAD3 exomes AF: 0.00117 AC: 291 AN: 247914 Hom.: 1 AF XY: 0.000820 AC XY: 110 AN XY: 134172

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.000504

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000473 AC: 685 AN: 1446762 Hom.: 7 Cov.: 27 AF XY: 0.000366 AC XY: 264 AN XY: 720496

Gnomad4 AFR exome AF: 0.0181

Gnomad4 AMR exome AF: 0.000520

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000127

Gnomad4 OTH exome AF: 0.000870

GnomAD4 genome AF: 0.00478 AC: 722 AN: 150990 Hom.: 4 Cov.: 31 AF XY: 0.00443 AC XY: 327 AN XY: 73734

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.000865

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000888

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.000515 Hom.: 0

Bravo AF: 0.00543

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00144 AC: 175

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.000110

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

RANBP17-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.2
DANN	Benign	0.76
DEOGEN2	Benign	0.00096	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.91	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.19		Gain of disorder (P = 0.0467);
MVP		0.57
MPC		0.025
ClinPred		0.0092	T
GERP RS		2.7
Varity_R		0.051
gMVP		0.18

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

Other links and lift over

dbSNP: rs148659070; hg19: chr5-170336722;