18-11851905-A-G

Variant names:

• chr18-11851905-A-G
• rs775796754
• NM_020412.5:c.394A>G

Variant summary

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

The NM_020412.5(CHMP1B):​c.394A>G​(p.Met132Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHMP1B NM_020412.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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]

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]

CHMP1B-AS1 (HGNC:52778): (CHMP1B antisense RNA 1)

ACMG classification

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 rank	MANE	Protein	UniProt
CHMP1B	NM_020412.5	c.394A>G	p.Met132Val	missense_variant	Exon 1 of 1	ENST00000526991.3	NP_065145.2
GNAL	NM_182978.4	c.723-10490A>G		intron_variant	Intron 5 of 11	ENST00000334049.11	NP_892023.1
GNAL	NM_001369387.1	c.492-10490A>G		intron_variant	Intron 5 of 11	ENST00000423027.8	NP_001356316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP1B	ENST00000526991.3	c.394A>G	p.Met132Val	missense_variant	Exon 1 of 1	6	NM_020412.5	ENSP00000432279.1
GNAL	ENST00000334049.11	c.723-10490A>G		intron_variant	Intron 5 of 11	1	NM_182978.4	ENSP00000334051.5
GNAL	ENST00000423027.8	c.492-10490A>G		intron_variant	Intron 5 of 11	1	NM_001369387.1	ENSP00000408489.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461676 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727124

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.394A>G (p.M132V) alteration is located in exon 1 (coding exon 1) of the CHMP1B gene. This alteration results from a A to G substitution at nucleotide position 394, causing the methionine (M) at amino acid position 132 to be replaced by a valine (V). 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	Benign	0.33
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.36	T
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.53
Sift	Benign	0.13	T
Sift4G	Benign	0.14	T
Polyphen		0.27	B
Vest4		0.78
MutPred		0.60		Gain of catalytic residue at M132 (P = 0.0084);
MVP		0.96
MPC		1.1
ClinPred		0.75	D
GERP RS		5.6
Varity_R		0.50
gMVP		0.77

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

Other links and lift over

dbSNP: rs775796754; hg19: chr18-11851904;