rs1553851490

Positions:

• chr3-179416531-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_021629.4(GNB4):​c.229G>A​(p.Gly77Arg) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNB4 NM_021629.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.80

Genes affected

GNB4 (HGNC:20731): (G protein subunit beta 4) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a repeat WD 1 (size 39) in uniprot entity GBB4_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_021629.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• PP5: Variant 3-179416531-C-T is Pathogenic according to our data. Variant chr3-179416531-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB4	NM_021629.4	c.229G>A	p.Gly77Arg	missense_variant	5/10	ENST00000232564.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB4	ENST00000232564.8	c.229G>A	p.Gly77Arg	missense_variant	5/10	1	NM_021629.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease dominant intermediate F Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 13, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 77 of the GNB4 protein (p.Gly77Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 34071515). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 488522). 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 GNB4 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.89	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.1	D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.016	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.66		Gain of methylation at K78 (P = 0.05);Gain of methylation at K78 (P = 0.05);Gain of methylation at K78 (P = 0.05);
MVP		0.87
MPC		1.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.50		Position offset: 25

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553851490; hg19: chr3-179134319; COSMIC: COSV51708434; COSMIC: COSV51708434;