11-134225226-A-G

Variant names:

• chr11-134225226-A-G
• NM_052875.5:c.104A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_052875.5(VPS26B):​c.104A>G​(p.Glu35Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS26B NM_052875.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.15

Genes affected

VPS26B (HGNC:28119): (VPS26 retromer complex component B) Predicted to be involved in intracellular protein transport and retrograde transport, endosome to Golgi. Predicted to act upstream of or within cellular response to interferon-gamma. Predicted to be located in early endosome and late endosome. Predicted to be part of retromer complex. Predicted to be active in endosome. [provided by Alliance of Genome Resources, Apr 2022]

NCAPD3 (HGNC:28952): (non-SMC condensin II complex subunit D3) Condensin complexes I and II play essential roles in mitotic chromosome assembly and segregation. Both condensins contain 2 invariant structural maintenance of chromosome (SMC) subunits, SMC2 (MIM 605576) and SMC4 (MIM 605575), but they contain different sets of non-SMC subunits. NCAPD3 is 1 of 3 non-SMC subunits that define condensin II (Ono et al., 2003 [PubMed 14532007]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27036965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS26B	NM_052875.5	c.104A>G	p.Glu35Gly	missense_variant	Exon 1 of 6	ENST00000281187.10	NP_443107.1
VPS26B	XM_011542565.4	c.104A>G	p.Glu35Gly	missense_variant	Exon 1 of 4		XP_011540867.1
NCAPD3	NM_001372070.1	c.-719T>C		5_prime_UTR_variant	Exon 1 of 37		NP_001358999.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS26B	ENST00000281187.10	c.104A>G	p.Glu35Gly	missense_variant	Exon 1 of 6	1	NM_052875.5	ENSP00000281187.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.104A>G (p.E35G) alteration is located in exon 1 (coding exon 1) of the VPS26B gene. This alteration results from a A to G substitution at nucleotide position 104, causing the glutamic acid (E) at amino acid position 35 to be replaced by a glycine (G). 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	Uncertain	0.43
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.036	D;D
Polyphen		0.44	B;B
Vest4		0.26
MutPred		0.53		Loss of solvent accessibility (P = 0.0477);Loss of solvent accessibility (P = 0.0477);
MVP		0.10
MPC		1.5
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.64
gMVP		0.68

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-134095120;