Genetic Variant RANBP3L:p.Val180Ile (chr5-36261985-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_145000.5(RANBP3L):c.538G>A(p.Val180Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,268 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: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RANBP3L
NM_145000.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.240

Publications

0 publications found

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.041841745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RANBP3L	NM_145000.5 link	c.538G>A	p.Val180Ile	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.538G>A	p.Val180Ile	missense_variant	Exon 7 of 14	1	NM_145000.5	ENSP00000296604.3	Q86VV4-1
RANBP3L	ENST00000502994.5 link	c.613G>A	p.Val205Ile	missense_variant	Exon 8 of 15	2		ENSP00000421853.1	Q86VV4-3
RANBP3L	ENST00000515759.5 link	c.538G>A	p.Val180Ile	missense_variant	Exon 7 of 10	2		ENSP00000421149.1	Q86VV4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455268

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724478

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33276

American (AMR)

AF:

0.00

AC:

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39524

South Asian (SAS)

AF:

0.00

AC:

AN:

85792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106798

Other (OTH)

AF:

0.00

AC:

AN:

60140

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 22, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.613G>A (p.V205I) alteration is located in exon 8 (coding exon 8) of the RANBP3L gene. This alteration results from a G to A substitution at nucleotide position 613, causing the valine (V) at amino acid position 205 to be replaced by an isoleucine (I). 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

0.075

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0027

T;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.042

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.73

N;.;N

PhyloP100

0.24

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.21

N;N;N

REVEL

Benign

0.060

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.44

T;T;T

Polyphen

0.0060

B;.;.

Vest4

0.039

MutPred

0.20

Gain of phosphorylation at S179 (P = 0.1632);.;Gain of phosphorylation at S179 (P = 0.1632);

MVP

0.030

MPC

0.081

ClinPred

0.084

GERP RS

1.3

Varity_R

0.034

gMVP

0.092

Mutation Taster

=95/5

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over