2-86529254-T-G

Variant names:

• chr2-86529254-T-G
• rs752418529
• NM_016079.4:c.250A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016079.4(CHMP3):​c.250A>C​(p.Met84Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. M84V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHMP3 NM_016079.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.93
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2917912).

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.250A>C	p.Met84Leu	missense	Exon 3 of 6	NP_057163.1	Q9Y3E7-1
	RNF103-CHMP3	NM_001198954.1		c.337A>C	p.Met113Leu	missense	Exon 5 of 8	NP_001185883.1	Q9Y3E7-3
	CHMP3	NM_001005753.3		c.52A>C	p.Met18Leu	missense	Exon 2 of 5	NP_001005753.1	Q9Y3E7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP3	ENST00000263856.9	TSL:1 MANE Select	c.250A>C	p.Met84Leu	missense	Exon 3 of 6	ENSP00000263856.4	Q9Y3E7-1
	RNF103-CHMP3	ENST00000604011.5	TSL:2	c.337A>C	p.Met113Leu	missense	Exon 5 of 8	ENSP00000474823.1
	CHMP3	ENST00000953402.1		c.250A>C	p.Met84Leu	missense	Exon 3 of 7	ENSP00000623461.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249036 AF XY: 0.00000742

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459994 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726356

African (AFR) AF: 0.00 AC: 0 AN: 33292

American (AMR) AF: 0.00 AC: 0 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39450

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 86002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111286

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Benign	0.73
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.035
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.38	N
PhyloP100		7.9
PROVEAN	Benign	0.14	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.74
MutPred		0.61		Loss of disorder (P = 0.0892)
MVP		0.52
MPC		0.18
ClinPred		0.34	T
GERP RS		6.0
Varity_R		0.42
gMVP		0.72
Mutation Taster		=8/92	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: rs752418529; hg19: chr2-86756377;