8-81758540-C-T

Variant names:

• chr8-81758540-C-T
• rs1432359376
• NM_152284.4:c.698C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152284.4(CHMP4C):​c.698C>T​(p.Thr233Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,454,190 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHMP4C NM_152284.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.64

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24007162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP4C	NM_152284.4	c.698C>T	p.Thr233Ile	missense_variant	Exon 5 of 5	ENST00000297265.5	NP_689497.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP4C	ENST00000297265.5	c.698C>T	p.Thr233Ile	missense_variant	Exon 5 of 5	1	NM_152284.4	ENSP00000297265.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250900 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135596

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454190 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.698C>T (p.T233I) alteration is located in exon 5 (coding exon 5) of the CHMP4C gene. This alteration results from a C to T substitution at nucleotide position 698, causing the threonine (T) at amino acid position 233 to be replaced by an isoleucine (I). 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	0.28
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.86	P
Vest4		0.20
MutPred		0.29		Loss of phosphorylation at T233 (P = 0.0554);
MVP		0.73
MPC		0.16
ClinPred		0.55	D
GERP RS		5.2
Varity_R		0.39
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs1432359376; hg19: chr8-82670775;