5-36269437-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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]

LOC124900962 (HGNC:):

ACMG classification

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	UniProt
RANBP3L	NM_145000.5	c.221G>A	p.Arg74Gln	missense_variant	4/14	ENST00000296604.8
LOC124900962	XR_007058733.1	n.127+27409C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP3L	ENST00000296604.8	c.221G>A	p.Arg74Gln	missense_variant	4/14	1	NM_145000.5	A2
RANBP3L	ENST00000502994.5	c.221G>A	p.Arg74Gln	missense_variant	4/15	2		P4
RANBP3L	ENST00000515759.5	c.221G>A	p.Arg74Gln	missense_variant	4/10	2
RANBP3L	ENST00000505865.1	c.221G>A	p.Arg74Gln	missense_variant	5/6	4

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152122 Hom.: 0 Cov.: 33

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: 15 AN: 251142 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135722

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: 67 AN: 1427072 Hom.: 0 Cov.: 26 AF XY: 0.0000435 AC XY: 31 AN XY: 712164

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: 10 AN: 152122 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74304

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.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.097	T;.;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.0049
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.7	M;M;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
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	D
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

Other links and lift over

dbSNP: rs774935712; hg19: chr5-36269539; COSMIC: COSV56955302;