Variant 2-86563309-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_016079.4(CHMP3):c.40G>A(p.Glu14Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CHMP3
NM_016079.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.61

Variant links:

Genes affected

CHMP3 (HGNC:29865): (charged multivesicular body protein 3) This gene encodes a protein that sorts transmembrane proteins into lysosomes/vacuoles via the multivesicular body (MVB) pathway. This protein, along with other soluble coiled-coil containing proteins, forms part of the ESCRT-III protein complex that binds to the endosomal membrane and recruits additional cofactors for protein sorting into the MVB. This protein may also co-immunoprecipitate with a member of the IFG-binding protein superfamily. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the upstream ring finger protein 103 (RNF103) gene. [provided by RefSeq, Nov 2010]

CHMP3 links:

RNF103-CHMP3 (HGNC:):

RNF103-CHMP3 links:

CHMP3-AS1 (HGNC:55795): (CHMP3 and RNF103 antisense RNA 1)

CHMP3-AS1 links:

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ACMG classification

Classification made for transcript

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
CHMP3	NM_016079.4 linkuse as main transcript	c.40G>A	p.Glu14Lys	missense_variant	1/6	ENST00000263856.9
RNF103-CHMP3	NM_001198954.1 linkuse as main transcript	c.133-20997G>A		intron_variant
CHMP3-AS1	NR_183900.1 linkuse as main transcript	n.253+531C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHMP3	ENST00000263856.9 linkuse as main transcript	c.40G>A	p.Glu14Lys	missense_variant	1/6	1	NM_016079.4	P1	Q9Y3E7-1
CHMP3-AS1	ENST00000439077.1 linkuse as main transcript	n.248+531C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727198

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Jul 14, 2023

The c.40G>A (p.E14K) alteration is located in exon 1 (coding exon 1) of the CHMP3 gene. This alteration results from a G to A substitution at nucleotide position 40, causing the glutamic acid (E) at amino acid position 14 to be replaced by a lysine (K). 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

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.5

M;M

MutationTaster

Benign

1.0

D;D;D;D

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.60

Sift

Benign

0.063

T;T

Sift4G

Uncertain

0.022

D;D

Polyphen

0.48

P;B

Vest4

0.76

MutPred

0.40

Gain of MoRF binding (P = 0.0033);Gain of MoRF binding (P = 0.0033);

MVP

0.85

ClinPred

0.98

GERP RS

5.8

Varity_R

0.69

gMVP

0.38

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over