rs869312825

Positions:

• chr1-1804548-T-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_002074.5(GNB1):​c.301A>G​(p.Met101Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNB1 NM_002074.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.84

Genes affected

GNB1 (HGNC:4396): (G protein subunit beta 1) Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a repeat WD 2 (size 30) in uniprot entity GBB1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002074.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNB1. . Gene score misZ 3.8328 (greater than the threshold 3.09). Trascript score misZ 3.4817 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 42.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846
• PP5: Variant 1-1804548-T-C is Pathogenic according to our data. Variant chr1-1804548-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 224717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1804548-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNB1	NM_002074.5	c.301A>G	p.Met101Val	missense_variant	7/12	ENST00000378609.9	NP_002065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNB1	ENST00000378609.9	c.301A>G	p.Met101Val	missense_variant	7/12	1	NM_002074.5	ENSP00000367872	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 42 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Feb 21, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wangler Lab, Baylor College of Medicine	-	This missense GNB1 variant at c.301A>G(p.M101V) was discovered on exome through the Texome Project (R01HG011795). It was reported in individuals with Intellectual developmental disorder, autosomal dominant 42 (PMID:27108799, 30194818) (PS4). This variant has not been observed in gnomAD (PM2). The variant was de novo (PS2). We classify this variant as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 16, 2022	- -

Hypotonia;C0036572:Seizure;na:Neurodevelopmental Disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 05, 2016

- -

Hypotonia;C0036572:Seizure;C0270834:Focal impaired awareness seizure;C0454641:Expressive language delay;C0494475:Bilateral tonic-clonic seizure;C0557874:Global developmental delay;C1836830:Developmental regression;C3714756:Intellectual disability;C4021219:Multifocal epileptiform discharges;C4023476:EEG with generalized epileptiform discharges Pathogenic:1

Pathogenic, no assertion criteria provided

research

Genomics And Bioinformatics Analysis Resource, Columbia University

Feb 10, 2016

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2021

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27108799, 30194818) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;T;T;T;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.2	M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.6	.;.;D;D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	.;.;D;D;D;D
Sift4G	Uncertain	0.023	D;T;D;.;.;.
Polyphen		0.52	P;.;P;.;.;.
Vest4		0.90
MutPred		0.63		Loss of catalytic residue at M101 (P = 0.0833);.;Loss of catalytic residue at M101 (P = 0.0833);.;Loss of catalytic residue at M101 (P = 0.0833);Loss of catalytic residue at M101 (P = 0.0833);
MVP		0.93
MPC		2.4
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.61

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: rs869312825; hg19: chr1-1735987;