chr20-33851938-G-T

Variant names:

• chr20-33851938-G-T
• rs138156622
• NM_176812.5:c.484-139G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0390
• 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: Benign. The variant received -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	c.484-139G>T		intron_variant	Intron 3 of 4	ENST00000217402.3	NP_789782.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 829 AN: 152194 Hom.: 3 Cov.: 32

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.: 50 AF XY: 0.00623 AC XY: 3001 AN XY: 481784

African (AFR) AF: 0.000389 AC: 9 AN: 23154

American (AMR) AF: 0.000549 AC: 24 AN: 43716

Ashkenazi Jewish (ASJ) AF: 0.0000892 AC: 2 AN: 22434

East Asian (EAS) AF: 0.00 AC: 0 AN: 37200

South Asian (SAS) AF: 0.0000269 AC: 2 AN: 74436

European-Finnish (FIN) AF: 0.0281 AC: 1295 AN: 46056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3092

European-Non Finnish (NFE) AF: 0.00704 AC: 4448 AN: 631832

Other (OTH) AF: 0.00513 AC: 219 AN: 42668

GnomAD4 genome AF: 0.00544 AC: 829 AN: 152312 Hom.: 3 Cov.: 32 AF XY: 0.00631 AC XY: 470 AN XY: 74472

African (AFR) AF: 0.00125 AC: 52 AN: 41566

American (AMR) AF: 0.000588 AC: 9 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.0257 AC: 273 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00714 AC: 486 AN: 68038

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00801 Hom.: 1

Bravo AF: 0.00324

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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
PhyloP100		0.039
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs138156622; hg19: chr20-32439744;