rs864622729

Variant names:

• chr3-179419406-C-T
• rs864622729
• NM_021629.4:c.196G>A
• GNB4 p.Asp66Asn

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BS2

The NM_021629.4(GNB4):​c.196G>A​(p.Asp66Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,436,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GNB4 NM_021629.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84
• Publications: 3 publications found

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]

GNB4 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease dominant intermediate F

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a repeat WD 1 (size 39) in uniprot entity GBB4_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_021629.4
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021629.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB4	NM_021629.4	MANE Select	c.196G>A	p.Asp66Asn	missense	Exon 4 of 10	NP_067642.1	Q9HAV0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB4	ENST00000232564.8	TSL:1 MANE Select	c.196G>A	p.Asp66Asn	missense	Exon 4 of 10	ENSP00000232564.3	Q9HAV0
	GNB4	ENST00000466899.6	TSL:1	c.196G>A	p.Asp66Asn	missense	Exon 3 of 8	ENSP00000420066.2	H7C5J5
	GNB4	ENST00000674862.1		c.196G>A	p.Asp66Asn	missense	Exon 4 of 10	ENSP00000502628.1	Q9HAV0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251126 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1436976 Hom.: 0 Cov.: 26 AF XY: 0.0000153 AC XY: 11 AN XY: 716674

African (AFR) AF: 0.0000304 AC: 1 AN: 32924

American (AMR) AF: 0.0000224 AC: 1 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.00 AC: 0 AN: 85690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.0000138 AC: 15 AN: 1089486

Other (OTH) AF: 0.00 AC: 0 AN: 59568

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease dominant intermediate F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.053	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.49
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs864622729;

hg19: chr3-179137194;

COSMIC: COSV99224402;

COSMIC: COSV99224402;