chr8-81758536-G-T

Variant names:

• chr8-81758536-G-T
• rs35094336
• NM_152284.4:c.694G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152284.4(CHMP4C):​c.694G>T​(p.Ala232Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A232T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHMP4C NM_152284.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.15
• Publications: 0 publications found

Genes affected

CHMP4C (HGNC:30599): (charged multivesicular body protein 4C) CHMP4C belongs to the chromatin-modifying protein/charged multivesicular body protein (CHMP) family. These proteins are components of ESCRT-III (endosomal sorting complex required for transport III), a complex involved in degradation of surface receptor proteins and formation of endocytic multivesicular bodies (MVBs). Some CHMPs have both nuclear and cytoplasmic/vesicular distributions, and one such CHMP, CHMP1A (MIM 164010), is required for both MVB formation and regulation of cell cycle progression (Tsang et al., 2006 [PubMed 16730941]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25993964).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152284.4. 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
	CHMP4C	NM_152284.4	MANE Select	c.694G>T	p.Ala232Ser	missense	Exon 5 of 5	NP_689497.1	Q96CF2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP4C	ENST00000297265.5	TSL:1 MANE Select	c.694G>T	p.Ala232Ser	missense	Exon 5 of 5	ENSP00000297265.4	Q96CF2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457092 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725166

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107748

Other (OTH) AF: 0.00 AC: 0 AN: 60232

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.21
Sift	Benign	0.056	T
Sift4G	Uncertain	0.033	D
Polyphen		0.95	P
Vest4		0.35
MutPred		0.15		Gain of phosphorylation at A232 (P = 0.0394)
MVP		0.74
MPC		0.15
ClinPred		0.93	D
GERP RS		6.1
Varity_R		0.65
gMVP		0.45
Mutation Taster		=33/67	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: rs35094336; hg19: chr8-82670771;