chr3-179401278-C-T

Position:

• chr3-179401278-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021629.4(GNB4):​c.958G>A​(p.Val320Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00308 in 1,613,740 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V320L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (26 hom.)
• Consequence: GNB4 NM_021629.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.93

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008676469).
• BP6: Variant 3-179401278-C-T is Benign according to our data. Variant chr3-179401278-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 414882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-179401278-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0034 (518/152160) while in subpopulation NFE AF= 0.0041 (279/68010). AF 95% confidence interval is 0.00371. There are 4 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 518 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB4	NM_021629.4	c.958G>A	p.Val320Ile	missense_variant	10/10	ENST00000232564.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB4	ENST00000232564.8	c.958G>A	p.Val320Ile	missense_variant	10/10	1	NM_021629.4	P1

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 518 AN: 152042 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0196

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00419 AC: 1053 AN: 251200 Hom.: 8 AF XY: 0.00407 AC XY: 553 AN XY: 135770

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000818

Gnomad FIN exome AF: 0.0211

Gnomad NFE exome AF: 0.00456

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00305 AC: 4455 AN: 1461580 Hom.: 26 Cov.: 30 AF XY: 0.00306 AC XY: 2222 AN XY: 727082

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.00278

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00340 AC: 518 AN: 152160 Hom.: 4 Cov.: 33 AF XY: 0.00406 AC XY: 302 AN XY: 74390

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.0196

Gnomad4 NFE AF: 0.00410

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00326 Hom.: 5

Bravo AF: 0.00144

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00443 AC: 538

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00208

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	GNB4: BS1, BS2 -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 23, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.073	T;T
Eigen	Benign	-0.068
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0087	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.23	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.90	N;N
REVEL	Benign	0.039
Sift	Benign	0.038	D;D
Sift4G	Uncertain	0.055	T;T
Polyphen		0.068	B;B
Vest4		0.13
MVP		0.37
MPC		0.51
ClinPred		0.021	T
GERP RS		4.0
Varity_R		0.13
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61750380; hg19: chr3-179119066;