9-33276474-G-C

Variant names:

• chr9-33276474-G-C
• rs1193046940
• NM_016410.6:c.406G>C

Variant summary

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

The NM_016410.6(CHMP5):​c.406G>C​(p.Glu136Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E136K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHMP5 NM_016410.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

CHMP5 (HGNC:26942): (charged multivesicular body protein 5) CHMP5 belongs to the chromatin-modifying protein/charged multivesicular body protein (CHMP) family. These proteins are components of ESCRT-III (endosomal sorting complex required for transport III), a complex involved in degradation of surface receptor proteins and formation of endocytic multivesicular bodies (MVBs). Some CHMPs have both nuclear and cytoplasmic/vesicular distributions, and one such CHMP, CHMP1A (MIM 164010), is required for both MVB formation and regulation of cell cycle progression (Tsang et al., 2006 [PubMed 16730941]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016410.6. 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
	CHMP5	NM_016410.6	MANE Select	c.406G>C	p.Glu136Gln	missense	Exon 6 of 8	NP_057494.3
	CHMP5	NM_001195536.2		c.406G>C	p.Glu136Gln	missense	Exon 6 of 7	NP_001182465.1	Q9NZZ3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP5	ENST00000223500.9	TSL:1 MANE Select	c.406G>C	p.Glu136Gln	missense	Exon 6 of 8	ENSP00000223500.7	Q9NZZ3-1
	CHMP5	ENST00000937845.1		c.445G>C	p.Glu149Gln	missense	Exon 7 of 9	ENSP00000607904.1
	CHMP5	ENST00000948350.1		c.433G>C	p.Glu145Gln	missense	Exon 8 of 10	ENSP00000618409.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

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	0.33
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.5	L
PhyloP100		10
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.34
Sift	Benign	0.38	T
Sift4G	Benign	0.53	T
Polyphen		0.26	B
Vest4		0.70
MutPred		0.53		Gain of helix (P = 0.0496)
MVP		0.75
MPC		0.58
ClinPred		0.73	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.39
Mutation Taster		=67/33	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

dbSNP: rs1193046940; hg19: chr9-33276472;