1-1806503-A-T

Position:

chr1-1806503-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong

The ENST00000378609.9(GNB1):c.239T>A(p.Ile80Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. I80S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GNB1
ENST00000378609.9 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 9.08

Variant links:

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]

GNB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000378609.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-1806503-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 391609.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, 0.836

PP5

Variant 1-1806503-A-T is Pathogenic according to our data. Variant chr1-1806503-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 224715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1806503-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNB1	NM_002074.5 linkuse as main transcript	c.239T>A	p.Ile80Asn	missense_variant	6/12	ENST00000378609.9	NP_002065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNB1	ENST00000378609.9 linkuse as main transcript	c.239T>A	p.Ile80Asn	missense_variant	6/12	1	NM_002074.5	ENSP00000367872	P1	P62873-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251124

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459226

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 42

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogeic with strong evidence (ClinVar ID: VCV000224715.5, PMID 27108799 and 25485910, PS1). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004). A different missense change at the same codon (p.Ile80Ser) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000391609.2, PM5).The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Missense changes are a common disease-causing mechanism (PP2). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Acute lymphoid leukemia

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2022	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: 224715). This missense change has been observed in individual(s) with GNB1-related conditions (PMID: 27108799, 32901917). In at least one individual the variant was observed to be de novo. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 80 of the GNB1 protein (p.Ile80Asn). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2024	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: 35119134, 25485910, 27108799, 32901917, 35719373, 34522861) -

Hypotonia;C0036572:Seizure;C0232466:Feeding difficulties;C0270834:Focal impaired awareness seizure;C0456070:Growth delay;C0557874:Global developmental delay;C1838391:Limb hypertonia;C1860834:Infantile muscular hypotonia;C2315100:Failure to thrive;C4021219:Multifocal epileptiform discharges;C4048268:Cerebral visual impairment

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Genomics And Bioinformatics Analysis Resource, Columbia University

Feb 10, 2016

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Benign

0.93

DEOGEN2

Uncertain

0.45

T;T;T;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;.;D;D;D

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.84

D;D;D;D;D

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.8

L;L;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.9

.;D;D;D;D

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

.;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;.;.;.

Polyphen

1.0

D;D;.;.;.

Vest4

0.91

MutPred

0.55

Loss of stability (P = 0.0339);Loss of stability (P = 0.0339);.;Loss of stability (P = 0.0339);Loss of stability (P = 0.0339);

MVP

0.89

MPC

4.6

ClinPred

0.99

GERP RS

4.5

Varity_R

0.97

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over