14-24211811-G-A

Variant names:

• chr14-24211811-G-A
• rs1594470213
• NM_014169.5:c.50C>T

Variant summary

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

The NM_014169.5(CHMP4A):​c.50C>T​(p.Pro17Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,308 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CHMP4A NM_014169.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.18

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=0.2675962).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP4A	NM_014169.5	c.50C>T	p.Pro17Leu	missense_variant	Exon 2 of 6	ENST00000347519.12	NP_054888.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP4A	ENST00000347519.12	c.50C>T	p.Pro17Leu	missense_variant	Exon 2 of 6	1	NM_014169.5	ENSP00000324205.11
ENSG00000254692	ENST00000530611.1	c.50C>T	p.Pro17Leu	missense_variant	Exon 2 of 10	2		ENSP00000433967.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461308 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727030

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.179C>T (p.P60L) alteration is located in exon 2 (coding exon 2) of the CHMP4A gene. This alteration results from a C to T substitution at nucleotide position 179, causing the proline (P) at amino acid position 60 to be replaced by a leucine (L). 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	0.12
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;.;T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.4	.;.;M;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.070	N;D;.;D
REVEL	Benign	0.20
Sift	Uncertain	0.010	.;D;.;D
Sift4G	Uncertain	0.0090	D;D;D;.
Polyphen		0.0030	.;.;B;.
Vest4		0.39
MutPred		0.22		.;Loss of glycosylation at P60 (P = 0.0556);.;.;
MVP		0.66
MPC		0.24
ClinPred		0.89	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1594470213; hg19: chr14-24681017;