9-33265146-C-T

Position:

• chr9-33265146-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016410.6(CHMP5):​c.68C>T​(p.Thr23Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHMP5 NM_016410.6 missense, splice_region
• Scores: Splicing: ADA: 0.5051
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.526

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24498442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP5	NM_016410.6	c.68C>T	p.Thr23Met	missense_variant, splice_region_variant	1/8	ENST00000223500.9	NP_057494.3
CHMP5	NM_001195536.2	c.68C>T	p.Thr23Met	missense_variant, splice_region_variant	1/7		NP_001182465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP5	ENST00000223500.9	c.68C>T	p.Thr23Met	missense_variant, splice_region_variant	1/8	1	NM_016410.6	ENSP00000223500.7
CHMP5	ENST00000419016.6	c.68C>T	p.Thr23Met	missense_variant, splice_region_variant	1/7	2		ENSP00000442725.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461804 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

May 30, 2023

The c.68C>T (p.T23M) alteration is located in exon 1 (coding exon 1) of the CHMP5 gene. This alteration results from a C to T substitution at nucleotide position 68, causing the threonine (T) at amino acid position 23 to be replaced by a methionine (M). 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	0.15
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.072
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.029	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.018	.;B
Vest4		0.51
MutPred		0.40		Loss of phosphorylation at T23 (P = 0.0442);Loss of phosphorylation at T23 (P = 0.0442);
MVP		0.61
MPC		0.38
ClinPred		0.85	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.51
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.010		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: chr9-33265144;