Genetic Variant CHMP4B:c.-75C>G (chr20-33811394-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_176812.5(CHMP4B):c.-75C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 1,232,268 control chromosomes in the GnomAD database, including 146,709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 18459 hom., cov: 29)

Exomes 𝑓: 0.48 ( 128250 hom. )

Consequence

CHMP4B
NM_176812.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0180

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 20-33811394-C-G is Benign according to our data. Variant chr20-33811394-C-G is described in ClinVar as [Benign]. Clinvar id is 1240673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP4B	NM_176812.5 link	c.-75C>G		5_prime_UTR_variant	Exon 1 of 5	ENST00000217402.3	NP_789782.1	Q9H444

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP4B	ENST00000217402 link	c.-75C>G		5_prime_UTR_variant	Exon 1 of 5	1	NM_176812.5	ENSP00000217402.2		Q9H444

Frequencies

GnomAD3 genomes

AF:

0.485

AC:

72585

AN:

149704

Hom.:

18460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.371

Gnomad AMI

AF:

0.501

Gnomad AMR

AF:

0.542

Gnomad ASJ

AF:

0.577

Gnomad EAS

AF:

0.905

Gnomad SAS

AF:

0.568

Gnomad FIN

AF:

0.574

Gnomad MID

AF:

0.669

Gnomad NFE

AF:

0.483

Gnomad OTH

AF:

0.546

GnomAD4 exome

AF:

0.478

AC:

517569

AN:

1082466

Hom.:

128250

Cov.:

AF XY:

0.481

AC XY:

249718

AN XY:

519132

show subpopulations

Gnomad4 AFR exome

AF:

0.365

Gnomad4 AMR exome

AF:

0.587

Gnomad4 ASJ exome

AF:

0.563

Gnomad4 EAS exome

AF:

0.912

Gnomad4 SAS exome

AF:

0.558

Gnomad4 FIN exome

AF:

0.582

Gnomad4 NFE exome

AF:

0.459

Gnomad4 OTH exome

AF:

0.501

GnomAD4 genome

AF:

0.485

AC:

72604

AN:

149802

Hom.:

18459

Cov.:

AF XY:

0.495

AC XY:

36189

AN XY:

73062

show subpopulations

Gnomad4 AFR

AF:

0.371

Gnomad4 AMR

AF:

0.542

Gnomad4 ASJ

AF:

0.577

Gnomad4 EAS

AF:

0.904

Gnomad4 SAS

AF:

0.569

Gnomad4 FIN

AF:

0.574

Gnomad4 NFE

AF:

0.483

Gnomad4 OTH

AF:

0.545

Alfa

AF:

0.463

Hom.:

2023

Bravo

AF:

0.481

Asia WGS

AF:

0.655

AC:

2203

AN:

3366

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.73

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over