Variant 9-33278155-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016410.6(CHMP5):c.539G>A(p.Ser180Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CHMP5
NM_016410.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.61

Variant links:

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]

CHMP5 links:

CHMP5 (HGNC:):

CHMP5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.13148081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP5	NM_016410.6 linkuse as main transcript	c.539G>A	p.Ser180Asn	missense_variant	7/8	ENST00000223500.9	NP_057494.3	Q9NZZ3-1
CHMP5	NM_001195536.2 linkuse as main transcript	c.496+1591G>A		intron_variant			NP_001182465.1	Q9NZZ3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CHMP5	ENST00000223500.9 linkuse as main transcript	c.539G>A	p.Ser180Asn	missense_variant	7/8	1	NM_016410.6	ENSP00000223500.7	Q9NZZ3-1
CHMP5	ENST00000419016.6 linkuse as main transcript	c.496+1591G>A		intron_variant		2		ENSP00000442725.1	Q9NZZ3-2
CHMP5	ENST00000487080.1 linkuse as main transcript	n.363G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251046

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1461122

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726822

show subpopulations

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:

0.000163

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2023

The c.539G>A (p.S180N) alteration is located in exon 7 (coding exon 7) of the CHMP5 gene. This alteration results from a G to A substitution at nucleotide position 539, causing the serine (S) at amino acid position 180 to be replaced by an asparagine (N). 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

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.45

Eigen

Benign

0.091

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.83

M_CAP

Benign

0.0087

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.2

REVEL

Benign

0.16

Sift

Benign

0.45

Sift4G

Benign

0.32

Polyphen

0.0010

Vest4

0.090

MutPred

0.41

Loss of phosphorylation at S180 (P = 0.0109);

MVP

0.63

MPC

0.32

ClinPred

0.24

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over