chr3-15074003-C-T

Variant names:

• chr3-15074003-C-T
• NM_022340.4:c.2134G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022340.4(RBSN):​c.2134G>A​(p.Glu712Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RBSN NM_022340.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25
• Publications: 0 publications found

Genes affected

RBSN (HGNC:20759): (rabenosyn, RAB effector) This gene encodes a protein that belongs to the FYVE zinc finger family of proteins. The encoded protein interacts with Ras-related proteins that regulate membrane trafficking. A missense mutation in this gene is associated with a defect in the early endocytic pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

RBSN Gene-Disease associations (from GenCC):

• congenital neutropenia-myelofibrosis-nephromegaly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289750 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18474996).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022340.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBSN	NM_022340.4	MANE Select	c.2134G>A	p.Glu712Lys	missense	Exon 14 of 14	NP_071735.2	Q9H1K0-1
	RBSN	NM_001302378.2		c.2134G>A	p.Glu712Lys	missense	Exon 13 of 13	NP_001289307.1	Q9H1K0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBSN	ENST00000253699.7	TSL:1 MANE Select	c.2134G>A	p.Glu712Lys	missense	Exon 14 of 14	ENSP00000253699.3	Q9H1K0-1
	RBSN	ENST00000945194.1		c.2224G>A	p.Glu742Lys	missense	Exon 14 of 14	ENSP00000615253.1
	RBSN	ENST00000476527.7	TSL:2	c.2134G>A	p.Glu712Lys	missense	Exon 13 of 13	ENSP00000422551.1	Q9H1K0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Benign	0.0088
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.23
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.022	D
Polyphen		0.0030	B
Vest4		0.40
MutPred		0.21		Gain of ubiquitination at E712 (P = 6e-04)
MVP		0.53
MPC		0.42
ClinPred		0.82	D
GERP RS		5.3
Varity_R		0.31
gMVP		0.14
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

hg19: chr3-15115510; COSMIC: COSV53794151; COSMIC: COSV53794151;