rs762716183

Variant names:

• chr2-86529388-C-G
• rs762716183
• NM_016079.4:c.116G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-86529388-C-G
• chr2-86529388-C-A
• chr2-86529388-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016079.4(CHMP3):​c.116G>C​(p.Arg39Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,443,062 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: 0.000036 (0 hom.)
• Consequence: CHMP3 NM_016079.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82
• Publications: 0 publications found

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:38847): (RNF103-CHMP3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring RNF103 (ring finger protein 103) and CHMP3 (charged multivesicular body protein 3) genes. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Oct 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016079.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP3	NM_016079.4	MANE Select	c.116G>C	p.Arg39Thr	missense	Exon 3 of 6	NP_057163.1	Q9Y3E7-1
	RNF103-CHMP3	NM_001198954.1		c.203G>C	p.Arg68Thr	missense	Exon 5 of 8	NP_001185883.1	Q9Y3E7-3
	CHMP3	NM_001193517.2		c.116G>C	p.Arg39Thr	missense	Exon 3 of 6	NP_001180446.1	Q9Y3E7-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP3	ENST00000263856.9	TSL:1 MANE Select	c.116G>C	p.Arg39Thr	missense	Exon 3 of 6	ENSP00000263856.4	Q9Y3E7-1
	RNF103-CHMP3	ENST00000604011.5	TSL:2	c.203G>C	p.Arg68Thr	missense	Exon 5 of 8	ENSP00000474823.1
	CHMP3	ENST00000953402.1		c.116G>C	p.Arg39Thr	missense	Exon 3 of 7	ENSP00000623461.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000429 AC: 1 AN: 233284 AF XY: 0.00000793

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000928

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000360 AC: 52 AN: 1443062 Hom.: 0 Cov.: 32 AF XY: 0.0000335 AC XY: 24 AN XY: 716966

African (AFR) AF: 0.00 AC: 0 AN: 32604

American (AMR) AF: 0.00 AC: 0 AN: 40768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 39054

South Asian (SAS) AF: 0.00 AC: 0 AN: 82574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.0000471 AC: 52 AN: 1104490

Other (OTH) AF: 0.00 AC: 0 AN: 59678

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.59
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.8
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.53
Sift	Benign	0.065	T
Sift4G	Benign	0.13	T
Polyphen		0.57	P
Vest4		0.81
MutPred		0.51		Gain of phosphorylation at R39 (P = 0.0412)
MVP		0.93
MPC		0.31
ClinPred		0.92	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.67
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs762716183; hg19: chr2-86756511;