Genetic Variant NM_176812.5:c.484-139G>T (chr20-33851938-G-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_176812.5(CHMP4B):c.484-139G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 1,076,900 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0054 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 50 hom. )

Consequence

CHMP4B
NM_176812.5 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0390

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 20-33851938-G-T is Benign according to our data. Variant chr20-33851938-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1214730.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 829 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP4B	NM_176812.5 link	c.484-139G>T		intron_variant	Intron 3 of 4	ENST00000217402.3	NP_789782.1	Q9H444

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP4B	ENST00000217402.3 link	c.484-139G>T		intron_variant	Intron 3 of 4	1	NM_176812.5	ENSP00000217402.2		Q9H444

Frequencies

GnomAD3 genomes

AF:

0.00545

AC:

829

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0257

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00714

Gnomad OTH

AF:

0.00335

GnomAD4 exome

AF:

0.00649

AC:

5999

AN:

924588

Hom.:

AF XY:

0.00623

AC XY:

3001

AN XY:

481784

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.000549

Gnomad4 ASJ exome

AF:

0.0000892

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000269

Gnomad4 FIN exome

AF:

0.0281

Gnomad4 NFE exome

AF:

0.00704

Gnomad4 OTH exome

AF:

0.00513

GnomAD4 genome

AF:

0.00544

AC:

829

AN:

152312

Hom.:

Cov.:

AF XY:

0.00631

AC XY:

470

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0257

Gnomad4 NFE

AF:

0.00714

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.00801

Hom.:

Bravo

AF:

0.00324

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 13, 2020

GeneDx

Significance: Likely 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

-0.85

CADD

Benign

5.2

DANN

Benign

0.76

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

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