Variant 5-36269437-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145000.5(RANBP3L):c.221G>A(p.Arg74Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,579,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

RANBP3L
NM_145000.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17836502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP3L	NM_145000.5 linkuse as main transcript	c.221G>A	p.Arg74Gln	missense_variant	4/14	ENST00000296604.8	NP_659437.3	Q86VV4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RANBP3L	ENST00000296604.8 linkuse as main transcript	c.221G>A	p.Arg74Gln	missense_variant	4/14	1	NM_145000.5	ENSP00000296604.3	Q86VV4-1
RANBP3L	ENST00000502994.5 linkuse as main transcript	c.221G>A	p.Arg74Gln	missense_variant	4/15	2		ENSP00000421853.1	Q86VV4-3
RANBP3L	ENST00000515759.5 linkuse as main transcript	c.221G>A	p.Arg74Gln	missense_variant	4/10	2		ENSP00000421149.1	Q86VV4-2
RANBP3L	ENST00000505865.1 linkuse as main transcript	c.221G>A	p.Arg74Gln	missense_variant	5/6	4		ENSP00000427147.1	D6RCM9

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251142

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000469

AC:

AN:

1427072

Hom.:

Cov.:

AF XY:

0.0000435

AC XY:

AN XY:

712164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000509

Gnomad4 OTH exome

AF:

0.0000675

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.221G>A (p.R74Q) alteration is located in exon 4 (coding exon 4) of the RANBP3L gene. This alteration results from a G to A substitution at nucleotide position 221, causing the arginine (R) at amino acid position 74 to be replaced by a glutamine (Q). 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

0.18

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.097

T;.;.;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.0049

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.7

M;M;M;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.2

N;N;D;D

REVEL

Benign

0.22

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.26

MutPred

0.40

Loss of catalytic residue at R74 (P = 0.0155);Loss of catalytic residue at R74 (P = 0.0155);Loss of catalytic residue at R74 (P = 0.0155);Loss of catalytic residue at R74 (P = 0.0155);

MVP

0.27

MPC

0.28

ClinPred

0.51

GERP RS

1.8

Varity_R

0.15

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over