18-11852106-G-A

Position:

• chr18-11852106-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020412.5(CHMP1B):​c.595G>A​(p.Val199Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,444,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHMP1B NM_020412.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079334825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP1B	NM_020412.5	c.595G>A	p.Val199Met	missense_variant	1/1	ENST00000526991.3	NP_065145.2
GNAL	NM_182978.4	c.723-10289G>A		intron_variant		ENST00000334049.11	NP_892023.1
GNAL	NM_001369387.1	c.492-10289G>A		intron_variant		ENST00000423027.8	NP_001356316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP1B	ENST00000526991.3	c.595G>A	p.Val199Met	missense_variant	1/1	6	NM_020412.5	ENSP00000432279.1
GNAL	ENST00000334049.11	c.723-10289G>A		intron_variant		1	NM_182978.4	ENSP00000334051.5
GNAL	ENST00000423027.8	c.492-10289G>A		intron_variant		1	NM_001369387.1	ENSP00000408489.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444852 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2023

The c.595G>A (p.V199M) 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 595, causing the valine (V) at amino acid position 199 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	Benign	0.15
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.54	T
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.010	N
REVEL	Uncertain	0.30
Sift	Benign	0.38	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.22
MutPred		0.18		Gain of MoRF binding (P = 0.1877);
MVP		0.61
MPC		0.59
ClinPred		0.38	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.084

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: rs761542966; hg19: chr18-11852105;