14-24211433-T-C

Position:

• chr14-24211433-T-C

Variant summary

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

The NM_014169.5(CHMP4A):​c.341A>G​(p.Lys114Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHMP4A NM_014169.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09

Genes affected

CHMP4A (HGNC:20274): (charged multivesicular body protein 4A) CHMP4A 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]

ENSG00000254692 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP4A	NM_014169.5	c.341A>G	p.Lys114Arg	missense_variant	3/6	ENST00000347519.12	NP_054888.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP4A	ENST00000347519.12	c.341A>G	p.Lys114Arg	missense_variant	3/6	1	NM_014169.5	ENSP00000324205.11
ENSG00000254692	ENST00000530611.1	c.341A>G	p.Lys114Arg	missense_variant	3/10	2		ENSP00000433967.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.470A>G (p.K157R) alteration is located in exon 3 (coding exon 3) of the CHMP4A gene. This alteration results from a A to G substitution at nucleotide position 470, causing the lysine (K) at amino acid position 157 to be replaced by an arginine (R). 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	0.10
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;.;D;T;D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.0099	T
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.7	.;.;.;M;.
MutationTaster	Benign	0.54	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.020	N;D;.;.;D
REVEL	Uncertain	0.52
Sift	Benign	0.047	.;D;.;.;T
Sift4G	Uncertain	0.042	D;D;D;D;.
Polyphen		0.29	.;.;.;B;.
Vest4		0.15
MutPred		0.68		.;Loss of ubiquitination at K157 (P = 0.0118);.;.;.;
MVP		0.57
MPC		0.14
ClinPred		0.85	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24680639;