1-1806514-A-T

Variant names:

• chr1-1806514-A-T
• NM_002074.5:c.228T>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_002074.5(GNB1):​c.228T>A​(p.Asp76Glu) variant causes a missense change involving the alteration of a non-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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D76G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNB1 NM_002074.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.55

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.

• PS1: Transcript NM_002074.5 (GNB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 224712
• 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 chr1-1806515-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.
• 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, 0.879
• PP5: Variant 1-1806514-A-T is Pathogenic according to our data. Variant chr1-1806514-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1699320.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNB1	NM_002074.5	c.228T>A	p.Asp76Glu	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.228T>A	p.Asp76Glu	missense_variant	Exon 6 of 12	1	NM_002074.5	ENSP00000367872.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 42 Pathogenic:1

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a suggested mechanism of disease in this gene and is associated with intellectual disability 42 (MIM#616973). However, a dominant-negative disease mechanism has not been excluded (PMID: 28087732, 32918542). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypes reported to have variability include epilepsy/seizures and brain abnormalities (PMID: 32918542). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Asp76Asn) and p.(Asp76Gly) variants were identified in unrelated patients with autosomal dominant intellectual disability 42 (MIM#616973). The p.(Asp76Gly) variant was shown to be due to a de novo event in one patient (ClinVar; PMID: 27108799). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in an unrelated individual. It has been reported to be de novo in a patient with intellectual disability 42 (MIM#616973). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	23
DANN	Benign	0.94
DEOGEN2	Benign	0.41	T;T;T;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;.;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.1	M;M;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.6	.;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;.;.;.
Polyphen		0.87	P;P;.;.;.
Vest4		0.98
MutPred		0.76		Gain of methylation at K78 (P = 0.0963);Gain of methylation at K78 (P = 0.0963);.;Gain of methylation at K78 (P = 0.0963);Gain of methylation at K78 (P = 0.0963);
MVP		0.98
MPC		2.0
ClinPred		0.99	D
GERP RS		0.76
Varity_R		0.94
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-1737953;