Variant 18-11851956-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.445G>A(p.Val149Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,598 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: 0.0000027 ( 0 hom. )

Consequence

CHMP1B
NM_020412.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.40

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:

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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.445G>A	p.Val149Met	missense_variant	1/1	ENST00000526991.3	NP_065145.2	Q7LBR1
GNAL	NM_182978.4 linkuse as main transcript	c.723-10439G>A		intron_variant		ENST00000334049.11	NP_892023.1	P38405-2
GNAL	NM_001369387.1 linkuse as main transcript	c.492-10439G>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.445G>A	p.Val149Met	missense_variant	1/1	6	NM_020412.5	ENSP00000432279.1	Q7LBR1
GNAL	ENST00000334049.11 linkuse as main transcript	c.723-10439G>A		intron_variant		1	NM_182978.4	ENSP00000334051.5	P38405-2
GNAL	ENST00000423027.8 linkuse as main transcript	c.492-10439G>A		intron_variant		1	NM_001369387.1	ENSP00000408489.2	P38405-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461598

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

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

Jun 13, 2023

The c.445G>A (p.V149M) 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 445, causing the valine (V) at amino acid position 149 to be replaced by a methionine (M). 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

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.096

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

0.66

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.64

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.46

MutPred

0.56

Loss of glycosylation at T144 (P = 0.2703);

MVP

0.89

MPC

1.5

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.78

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over