chr14-24211477-A-T

Variant names:

• chr14-24211477-A-T
• NM_014169.5:c.297T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014169.5(CHMP4A):​c.297T>A​(p.Asn99Lys) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHMP4A NM_014169.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP4A	NM_014169.5	c.297T>A	p.Asn99Lys	missense_variant	Exon 3 of 6	ENST00000347519.12	NP_054888.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP4A	ENST00000347519.12	c.297T>A	p.Asn99Lys	missense_variant	Exon 3 of 6	1	NM_014169.5	ENSP00000324205.11
ENSG00000254692	ENST00000530611.1	c.297T>A	p.Asn99Lys	missense_variant	Exon 3 of 10	2		ENSP00000433967.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.426T>A (p.N142K) alteration is located in exon 3 (coding exon 3) of the CHMP4A gene. This alteration results from a T to A substitution at nucleotide position 426, causing the asparagine (N) at amino acid position 142 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	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	.;.;D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.64	D
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	3.8	.;.;H;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.040	N;D;.;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	.;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;.
Polyphen		1.0	.;.;D;.
Vest4		0.27
MutPred		0.76		.;Loss of helix (P = 0.0167);.;.;
MVP		0.63
MPC		0.29
ClinPred		0.97	D
GERP RS		0.75
Varity_R		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr14-24680683;