Genetic Variant NM_176812.5:c.-75C>T (chr20-33811394-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_176812.5(CHMP4B):c.-75C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,084,638 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: 29)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

CHMP4B
NM_176812.5 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0180

Publications

9 publications found

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:

ZNF341-AS1 (HGNC:50736): (ZNF341 antisense RNA 1)

ZNF341-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176812.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP4B	NM_176812.5	MANE Select	c.-75C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_789782.1	Q9H444
	CHMP4B	NM_176812.5	MANE Select	c.-75C>T		5_prime_UTR	Exon 1 of 5	NP_789782.1	Q9H444

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHMP4B	ENST00000217402.3	TSL:1 MANE Select	c.-75C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000217402.2	Q9H444
CHMP4B	ENST00000217402.3	TSL:1 MANE Select	c.-75C>T	5_prime_UTR	Exon 1 of 5	ENSP00000217402.2	Q9H444
CHMP4B	ENST00000873319.1		c.-75C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000543378.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1084638

Hom.:

Cov.:

AF XY:

0.00000192

AC XY:

AN XY:

520128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21616

American (AMR)

AF:

0.00

AC:

AN:

7902

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13824

East Asian (EAS)

AF:

0.00

AC:

AN:

25300

South Asian (SAS)

AF:

0.00

AC:

AN:

31294

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2892

European-Non Finnish (NFE)

AF:

0.00000220

AC:

AN:

907158

Other (OTH)

AF:

0.00

AC:

AN:

43364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

-0.018

PromoterAI

-0.050

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

3.4

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over