9-33276474-G-C

Position:

• chr9-33276474-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• 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

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP5	NM_016410.6	c.406G>C	p.Glu136Gln	missense_variant	6/8	ENST00000223500.9	NP_057494.3
CHMP5	NM_001195536.2	c.406G>C	p.Glu136Gln	missense_variant	6/7		NP_001182465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP5	ENST00000223500.9	c.406G>C	p.Glu136Gln	missense_variant	6/8	1	NM_016410.6	ENSP00000223500.7
CHMP5	ENST00000419016.6	c.406G>C	p.Glu136Gln	missense_variant	6/7	2		ENSP00000442725.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

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

Nov 03, 2022

The c.406G>C (p.E136Q) alteration is located in exon 6 (coding exon 6) of the CHMP5 gene. This alteration results from a G to C substitution at nucleotide position 406, causing the glutamic acid (E) at amino acid position 136 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	0.33
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;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.38	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.26	.;B
Vest4		0.70
MutPred		0.53		Gain of helix (P = 0.0496);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

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: chr9-33276472;