14-24210707-G-T

Variant names:

• chr14-24210707-G-T
• NM_014169.5:c.421C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014169.5(CHMP4A):​c.421C>A​(p.Gln141Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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)
• Consequence: CHMP4A NM_014169.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32039067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP4A	NM_014169.5	c.421C>A	p.Gln141Lys	missense_variant	Exon 4 of 6	ENST00000347519.12	NP_054888.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP4A	ENST00000347519.12	c.421C>A	p.Gln141Lys	missense_variant	Exon 4 of 6	1	NM_014169.5	ENSP00000324205.11
ENSG00000254692	ENST00000530611.1	c.421C>A	p.Gln141Lys	missense_variant	Exon 4 of 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

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.550C>A (p.Q184K) alteration is located in exon 4 (coding exon 4) of the CHMP4A gene. This alteration results from a C to A substitution at nucleotide position 550, causing the glutamine (Q) at amino acid position 184 to be replaced by a lysine (K). 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	0.21
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;.;T;T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Benign	-0.28	T
MutationAssessor	Uncertain	2.1	.;.;.;M;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.030	N;N;.;.;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	.;D;.;.;D
Sift4G	Uncertain	0.0090	D;D;D;D;.
Polyphen		0.60	.;.;.;P;.
Vest4		0.24
MutPred		0.66		.;Gain of ubiquitination at Q184 (P = 0.0128);.;.;.;
MVP		0.48
MPC		0.12
ClinPred		0.72	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18

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: chr14-24679913;