20-33848495-G-T

Variant names:

• chr20-33848495-G-T
• NM_176812.5:c.219G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_176812.5(CHMP4B):​c.219G>T​(p.Lys73Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHMP4B NM_176812.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04
• Publications: 0 publications found

Genes affected

CHMP4B (HGNC:16171): (charged multivesicular body protein 4B) This gene encodes a member of the chromatin-modifying protein/charged multivesicular body protein (CHMP) protein family. The protein is part of the endosomal sorting complex required for transport (ESCRT) complex III (ESCRT-III), which functions in the sorting of endocytosed cell-surface receptors into multivesicular endosomes. The ESCRT machinery also functions in the final abscisson stage of cytokinesis and in the budding of enveloped viruses such as HIV-1. The three proteins of the CHMP4 subfamily interact with programmed cell death 6 interacting protein (PDCD6IP, also known as ALIX), which also functions in the ESCRT pathway. The CHMP4 proteins assemble into membrane-attached 5-nm filaments that form circular scaffolds and promote or stabilize outward budding. These polymers are proposed to help generate the luminal vesicles of multivesicular bodies. Mutations in this gene result in autosomal dominant posterior polar cataracts.[provided by RefSeq, Oct 2009]

CHMP4B Gene-Disease associations (from GenCC):

• cataract 31 multiple types

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior subcapsular cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.3781 (below the threshold of 3.09). Trascript score misZ: 2.8898 (below the threshold of 3.09). GenCC associations: The gene is linked to early-onset posterior subcapsular cataract, cataract 31 multiple types, early-onset posterior polar cataract.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP4B	NM_176812.5	c.219G>T	p.Lys73Asn	missense_variant	Exon 2 of 5	ENST00000217402.3	NP_789782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP4B	ENST00000217402.3	c.219G>T	p.Lys73Asn	missense_variant	Exon 2 of 5	1	NM_176812.5	ENSP00000217402.2

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 provided Uncertain:1

May 16, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.034	D
Polyphen		0.87	P
Vest4		0.85
MutPred		0.62		Loss of methylation at K73 (P = 0.0329);
MVP		0.92
MPC		2.4
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.88
gMVP		0.93
Mutation Taster		=16/84	disease causing

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

Other links and lift over

hg19: chr20-32436301;