2-86529365-A-C

Position:

• chr2-86529365-A-C

Variant summary

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

The NM_016079.4(CHMP3):​c.139T>G​(p.Ser47Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHMP3 NM_016079.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.22

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]

RNF103-CHMP3 (HGNC:):

ACMG classification

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	Protein	UniProt
CHMP3	NM_016079.4	c.139T>G	p.Ser47Ala	missense_variant	3/6	ENST00000263856.9	NP_057163.1
RNF103-CHMP3	NM_001198954.1	c.226T>G	p.Ser76Ala	missense_variant	5/8		NP_001185883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP3	ENST00000263856.9	c.139T>G	p.Ser47Ala	missense_variant	3/6	1	NM_016079.4	ENSP00000263856	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Nov 18, 2022

The c.139T>G (p.S47A) alteration is located in exon 3 (coding exon 3) of the CHMP3 gene. This alteration results from a T to G substitution at nucleotide position 139, causing the serine (S) at amino acid position 47 to be replaced by an alanine (A). 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	0.12
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Uncertain	0.031	D
MutationAssessor	Benign	1.6	L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Uncertain	-2.7	D;D;.;N
REVEL	Uncertain	0.38
Sift	Benign	0.18	T;T;.;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.028	B;P;.;.
Vest4		0.67
MutPred		0.40		Loss of phosphorylation at S47 (P = 0.0069);Loss of phosphorylation at S47 (P = 0.0069);.;.;
MVP		0.86
MPC		0.17
ClinPred		0.90	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.22

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: chr2-86756488;