rs149798652

chr3-179419416-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021629.4(GNB4):c.186T>C(p.His62=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,605,316 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (13 hom.)
• Consequence: GNB4 NM_021629.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.154

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 3-179419416-A-G is Benign according to our data. Variant chr3-179419416-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 414884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-179419416-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.154 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00152 (232/152352) while in subpopulation NFE AF= 0.00276 (188/68020). AF 95% confidence interval is 0.00244. There are 0 homozygotes in gnomad4. There are 101 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 232 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB4	NM_021629.4	c.186T>C	p.His62=	synonymous_variant	4/10	ENST00000232564.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB4	ENST00000232564.8	c.186T>C	p.His62=	synonymous_variant	4/10	1	NM_021629.4	P1

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 232 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00171 AC: 431 AN: 251336 Hom.: 0 AF XY: 0.00185 AC XY: 251 AN XY: 135826

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00286

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00186 AC: 2706 AN: 1452964 Hom.: 13 Cov.: 28 AF XY: 0.00194 AC XY: 1405 AN XY: 723556

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00468

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.000505

Gnomad4 NFE exome AF: 0.00213

Gnomad4 OTH exome AF: 0.00135

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.00136 AC XY: 101 AN XY: 74514

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00276

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00250 Hom.: 0

Bravo AF: 0.00140

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	GNB4: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2022	This variant is associated with the following publications: (PMID: 28975462) -

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

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	1.2
Dann	Benign	0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs149798652; hg19: chr3-179137204; COSMIC: COSV51709263; COSMIC: COSV51709263;