chr5-36260854-T-C

Position:

• chr5-36260854-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145000.5(RANBP3L):​c.595A>G​(p.Asn199Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000378 in 1,322,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: RANBP3L NM_145000.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09

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=0.093317956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RANBP3L	NM_145000.5	c.595A>G	p.Asn199Asp	missense_variant	8/14	ENST00000296604.8	NP_659437.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RANBP3L	ENST00000296604.8	c.595A>G	p.Asn199Asp	missense_variant	8/14	1	NM_145000.5	ENSP00000296604.3
RANBP3L	ENST00000502994.5	c.670A>G	p.Asn224Asp	missense_variant	9/15	2		ENSP00000421853.1
RANBP3L	ENST00000515759.5	c.595A>G	p.Asn199Asp	missense_variant	8/10	2		ENSP00000421149.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000378 AC: 5 AN: 1322944 Hom.: 0 Cov.: 20 AF XY: 0.00000603 AC XY: 4 AN XY: 663308

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000129

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Aug 28, 2024

The c.670A>G (p.N224D) alteration is located in exon 9 (coding exon 9) of the RANBP3L gene. This alteration results from a A to G substitution at nucleotide position 670, causing the asparagine (N) at amino acid position 224 to be replaced by an aspartic acid (D). 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	0.068
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0026	T;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.067
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.093	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.86	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.24
MutPred		0.24		Gain of disorder (P = 0.15);.;Gain of disorder (P = 0.15);
MVP		0.048
MPC		0.11
ClinPred		0.064	T
GERP RS		4.1
Varity_R		0.11
gMVP		0.11

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

LitVar

Other links and lift over

dbSNP: rs1409058579; hg19: chr5-36260956;