9-33265146-C-A

Variant names:

• chr9-33265146-C-A
• rs1820691841
• NM_016410.6:c.68C>A

Variant summary

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

The NM_016410.6(CHMP5):​c.68C>A​(p.Thr23Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T23M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHMP5 NM_016410.6 missense, splice_region
• Scores: Splicing: ADA: 0.003457
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.526
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.162557).

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.68C>A	p.Thr23Lys	missense splice_region	Exon 1 of 8	NP_057494.3
	CHMP5	NM_001195536.2		c.68C>A	p.Thr23Lys	missense splice_region	Exon 1 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.68C>A	p.Thr23Lys	missense splice_region	Exon 1 of 8	ENSP00000223500.7	Q9NZZ3-1
	CHMP5	ENST00000937845.1		c.68C>A	p.Thr23Lys	missense splice_region	Exon 1 of 9	ENSP00000607904.1
	CHMP5	ENST00000948350.1		c.68C>A	p.Thr23Lys	missense splice_region	Exon 2 of 10	ENSP00000618409.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.14	N
PhyloP100		0.53
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.31
Sift	Benign	0.65	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.32
MutPred		0.45		Gain of ubiquitination at T23 (P = 0.0121)
MVP		0.52
MPC		0.42
ClinPred		0.81	D
GERP RS		4.7
PromoterAI		0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.38
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0035
dbscSNV1_RF	Benign	0.13
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: rs1820691841; hg19: chr9-33265144;