rs869312821

Variant names:

• chr1-1806515-T-C
• rs869312821
• NM_002074.5:c.227A>G

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain 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 the GNB1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 3.8328 (above the threshold of 3.09). Trascript score misZ: 3.4817 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
GNB1	NM_002074.5	c.227A>G	p.Asp76Gly	missense_variant	Exon 6 of 12	ENST00000378609.9	NP_002065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB1	ENST00000378609.9	c.227A>G	p.Asp76Gly	missense_variant	Exon 6 of 12	1	NM_002074.5	ENSP00000367872.3

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

Jun 29, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). ClinVar contains an entry for this variant (Variation ID: 224711). 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. 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. 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). For these reasons, this variant has been classified as Pathogenic. -

Intellectual disability, autosomal dominant 42 Pathogenic:1

Nov 02, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Acute lymphoid leukemia Pathogenic:1

Nov 02, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

May 05, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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

Feb 10, 2016

Genomics And Bioinformatics Analysis Resource, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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;.;.;.
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;