Genetic Variant RANBP3L:p.Gln186Arg (chr5-36261966-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_145000.5(RANBP3L):c.557A>G(p.Gln186Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000865 in 1,595,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

RANBP3L
NM_145000.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0950

Variant links:

Genes affected

RANBP3L (HGNC:26353): (RAN binding protein 3 like) Enables SMAD binding activity. Predicted to be involved in several processes, including mesenchymal cell differentiation involved in bone development; negative regulation of osteoblast differentiation; and positive regulation of myoblast differentiation. Predicted to be part of nuclear pore. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RANBP3L links:

LOC124900962 (HGNC:):

LOC124900962 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.043117702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP3L	NM_145000.5 link	c.557A>G	p.Gln186Arg	missense_variant	Exon 7 of 14	ENST00000296604.8	NP_659437.3	Q86VV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RANBP3L	ENST00000296604.8 link	c.557A>G	p.Gln186Arg	missense_variant	Exon 7 of 14	1	NM_145000.5	ENSP00000296604.3	Q86VV4-1
RANBP3L	ENST00000502994.5 link	c.632A>G	p.Gln211Arg	missense_variant	Exon 8 of 15	2		ENSP00000421853.1	Q86VV4-3
RANBP3L	ENST00000515759.5 link	c.557A>G	p.Gln186Arg	missense_variant	Exon 7 of 10	2		ENSP00000421149.1	Q86VV4-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000108

AC:

AN:

248886

AF XY:

0.000134

show subpopulations

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:

0.000203

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000901

AC:

130

AN:

1443402

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

719258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33004

American (AMR)

AF:

0.00

AC:

AN:

44244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25950

East Asian (EAS)

AF:

0.00

AC:

AN:

39434

South Asian (SAS)

AF:

0.000235

AC:

AN:

85052

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0000939

AC:

103

AN:

1096904

Other (OTH)

AF:

0.000100

AC:

AN:

59708

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000655

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.632A>G (p.Q211R) alteration is located in exon 8 (coding exon 8) of the RANBP3L gene. This alteration results from a A to G substitution at nucleotide position 632, causing the glutamine (Q) at amino acid position 211 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0043

T;.;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.043

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

L;.;L

PhyloP100

-0.095

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.058

Sift

Benign

0.55

T;T;T

Sift4G

Benign

0.46

T;T;T

Polyphen

0.011

B;.;.

Vest4

0.33

MVP

0.030

MPC

0.11

ClinPred

0.14

GERP RS

-0.41

Varity_R

0.036

gMVP

0.21

Mutation Taster

=96/4

polymorphism

(source)

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

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5-36261966-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over