rs869312821

Positions:

• chr1-1806515-T-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_002074.5(GNB1):​c.227A>G​(p.Asp76Gly) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D76E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNB1 NM_002074.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.82

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 17 ACMG points.

• PM1: In a turn (size 2) in uniprot entity GBB1_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_002074.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-1806516-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 976696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.92
• PP5: Variant 1-1806515-T-C is Pathogenic according to our data. Variant chr1-1806515-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 224711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1806515-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB1	NM_002074.5	c.227A>G	p.Asp76Gly	missense_variant	6/12	ENST00000378609.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB1	ENST00000378609.9	c.227A>G	p.Asp76Gly	missense_variant	6/12	1	NM_002074.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 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: 27535533, 27108799) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	This variant disrupts the p.Asp76 amino acid residue in GNB1. Other variant(s) that disrupt this residue have been observed in individuals with GNB1-related conditions (PMID: 27108799), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNB1 protein function. ClinVar contains an entry for this variant (Variation ID: 224711). This missense change has been observed in individual(s) with intellectual disability syndrome (PMID: 27108799). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 76 of the GNB1 protein (p.Asp76Gly). -

Intellectual disability, autosomal dominant 42 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 02, 2021

- -

Acute lymphoid leukemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 02, 2021

- -

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;C0557874:Global developmental delay;C1860834:Infantile muscular hypotonia;C3714756:Intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

research

Genomics And Bioinformatics Analysis Resource, Columbia University

Feb 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.46	T;T;T;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.0	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.2	.;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Uncertain	0.029	D;D;.;.;.
Polyphen		0.63	P;P;.;.;.
Vest4		0.98
MutPred		0.71		Gain of MoRF binding (P = 0.0784);Gain of MoRF binding (P = 0.0784);.;Gain of MoRF binding (P = 0.0784);Gain of MoRF binding (P = 0.0784);
MVP		0.99
MPC		2.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.98

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: rs869312821; hg19: chr1-1737954; COSMIC: COSV66099716;