chr5-170911066-T-C

Position:

• chr5-170911066-T-C

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.692T>C​(p.Ile231Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00268 in 1,612,076 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0027 (28 hom.)
• Consequence: RANBP17 NM_022897.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.25

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=0.012865514).
• BP6: Variant 5-170911066-T-C is Benign according to our data. Variant chr5-170911066-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2656072.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-170911066-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0027 (3947/1460236) while in subpopulation MID AF= 0.0348 (200/5748). AF 95% confidence interval is 0.0308. There are 28 homozygotes in gnomad4_exome. There are 2106 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP17	NM_022897.5	c.692T>C	p.Ile231Thr	missense_variant	7/28	ENST00000523189.6	NP_075048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANBP17	ENST00000523189.6	c.692T>C	p.Ile231Thr	missense_variant	7/28	1	NM_022897.5	ENSP00000427975	P1

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 373 AN: 151722 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00691

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.00685

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00199

Gnomad OTH AF: 0.00818

GnomAD3 exomes AF: 0.00289 AC: 724 AN: 250392 Hom.: 6 AF XY: 0.00316 AC XY: 428 AN XY: 135326

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00282

Gnomad ASJ exome AF: 0.00786

Gnomad EAS exome AF: 0.000817

Gnomad SAS exome AF: 0.00651

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00253

Gnomad OTH exome AF: 0.00640

GnomAD4 exome AF: 0.00270 AC: 3947 AN: 1460236 Hom.: 28 Cov.: 31 AF XY: 0.00290 AC XY: 2106 AN XY: 726406

Gnomad4 AFR exome AF: 0.000957

Gnomad4 AMR exome AF: 0.00307

Gnomad4 ASJ exome AF: 0.00836

Gnomad4 EAS exome AF: 0.000580

Gnomad4 SAS exome AF: 0.00665

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00220

Gnomad4 OTH exome AF: 0.00516

GnomAD4 genome AF: 0.00246 AC: 373 AN: 151840 Hom.: 1 Cov.: 31 AF XY: 0.00267 AC XY: 198 AN XY: 74250

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.00690

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00117

Gnomad4 SAS AF: 0.00706

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00199

Gnomad4 OTH AF: 0.00857

Alfa AF: 0.00263 Hom.: 2

Bravo AF: 0.00267

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00264 AC: 320

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.00306

EpiControl AF: 0.00392

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

RANBP17: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.78	P
Vest4		0.61
MVP		0.72
MPC		0.029
ClinPred		0.073	T
GERP RS		4.3
Varity_R		0.40
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs139981430; hg19: chr5-170338070;