2-86529388-C-T

Variant names:

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

Variant summary

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

The NM_016079.4(CHMP3):​c.116G>A​(p.Arg39Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,062 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R39T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHMP3 NM_016079.4 missense
• Clinical Significance: Not reported in ClinVar
• 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>A	p.Arg39Lys	missense	Exon 3 of 6	NP_057163.1	Q9Y3E7-1
	RNF103-CHMP3	NM_001198954.1		c.203G>A	p.Arg68Lys	missense	Exon 5 of 8	NP_001185883.1	Q9Y3E7-3
	CHMP3	NM_001193517.2		c.116G>A	p.Arg39Lys	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>A	p.Arg39Lys	missense	Exon 3 of 6	ENSP00000263856.4	Q9Y3E7-1
	RNF103-CHMP3	ENST00000604011.5	TSL:2	c.203G>A	p.Arg68Lys	missense	Exon 5 of 8	ENSP00000474823.1
	CHMP3	ENST00000953402.1		c.116G>A	p.Arg39Lys	missense	Exon 3 of 7	ENSP00000623461.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443062 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 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: 0.0000121 AC: 1 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: 0.00 AC: 0 AN: 1104490

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.8
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.38
Sift	Benign	0.056	T
Sift4G	Benign	0.070	T
Polyphen		0.64	P
Vest4		0.64
MutPred		0.49		Gain of ubiquitination at R39 (P = 0.0289)
MVP		0.95
MPC		0.26
ClinPred		0.86	D
GERP RS		6.1
Varity_R		0.75
gMVP		0.58
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs762716183; hg19: chr2-86756511;