9-33265088-C-T

Position:

• chr9-33265088-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_016410.6(CHMP5):​c.10C>T​(p.Leu4Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHMP5 NM_016410.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.523

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17728102).
• BP6: Variant 9-33265088-C-T is Benign according to our data. Variant chr9-33265088-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3144462.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP5	NM_016410.6	c.10C>T	p.Leu4Phe	missense_variant	1/8	ENST00000223500.9	NP_057494.3
CHMP5	NM_001195536.2	c.10C>T	p.Leu4Phe	missense_variant	1/7		NP_001182465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP5	ENST00000223500.9	c.10C>T	p.Leu4Phe	missense_variant	1/8	1	NM_016410.6	ENSP00000223500.7
CHMP5	ENST00000419016.6	c.10C>T	p.Leu4Phe	missense_variant	1/7	2		ENSP00000442725.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Uncertain	0.42	.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.14
Sift	Benign	0.14	T;T
Sift4G	Benign	0.092	T;T
Polyphen		0.0	.;B
Vest4		0.092
MutPred		0.46		Loss of stability (P = 0.0978);Loss of stability (P = 0.0978);
MVP		0.47
MPC		0.38
ClinPred		0.50	D
GERP RS		0.44
Varity_R		0.16
gMVP		0.37

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: chr9-33265086;