Variant 18-11851638-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020412.5(CHMP1B):c.127G>A(p.Gly43Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CHMP1B
NM_020412.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.50

Variant links:

Genes affected

CHMP1B (HGNC:24287): (charged multivesicular body protein 1B) CHMP1B belongs to the chromatin-modifying protein/charged multivesicular body protein (CHMP) family. These proteins are components of ESCRT-III (endosomal sorting complex required for transport III), a complex involved in degradation of surface receptor proteins and formation of endocytic multivesicular bodies (MVBs). Some CHMPs have both nuclear and cytoplasmic/vesicular distributions, and one such CHMP, CHMP1A (MIM 164010), is required for both MVB formation and regulation of cell cycle progression (Tsang et al., 2006 [PubMed 16730941]).[supplied by OMIM, Mar 2008]

CHMP1B links:

GNAL (HGNC:4388): (G protein subunit alpha L) This gene encodes a stimulatory G protein alpha subunit which mediates odorant signaling in the olfactory epithelium. This protein couples dopamine type 1 receptors and adenosine A2A receptors and is widely expressed in the central nervous system. Mutations in this gene have been associated with dystonia 25 and this gene is located in a susceptibility region for bipolar disorder and schizophrenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

GNAL links:

CHMP1B-AS1 (HGNC:):

CHMP1B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP1B	NM_020412.5 linkuse as main transcript	c.127G>A	p.Gly43Ser	missense_variant	1/1	ENST00000526991.3	NP_065145.2	Q7LBR1
GNAL	NM_182978.4 linkuse as main transcript	c.723-10757G>A		intron_variant		ENST00000334049.11	NP_892023.1	P38405-2
GNAL	NM_001369387.1 linkuse as main transcript	c.492-10757G>A		intron_variant		ENST00000423027.8	NP_001356316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CHMP1B	ENST00000526991.3 linkuse as main transcript	c.127G>A	p.Gly43Ser	missense_variant	1/1	6	NM_020412.5	ENSP00000432279.1	Q7LBR1
GNAL	ENST00000334049.11 linkuse as main transcript	c.723-10757G>A		intron_variant		1	NM_182978.4	ENSP00000334051.5	P38405-2
GNAL	ENST00000423027.8 linkuse as main transcript	c.492-10757G>A		intron_variant		1	NM_001369387.1	ENSP00000408489.2	P38405-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249112

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135168

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461690

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.127G>A (p.G43S) alteration is located in exon 1 (coding exon 1) of the CHMP1B gene. This alteration results from a G to A substitution at nucleotide position 127, causing the glycine (G) at amino acid position 43 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.068

MetaRNN

Uncertain

0.55

MetaSVM

Uncertain

0.60

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.64

Sift

Benign

0.061

Sift4G

Benign

0.092

Polyphen

0.98

Vest4

0.38

MutPred

0.64

Gain of phosphorylation at G43 (P = 0.0505);

MVP

0.83

MPC

1.5

ClinPred

0.98

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.66

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