rs1078749

Variant names:

• chr3-179426153-A-G
• rs1078749
• NM_021629.4:c.48T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021629.4(GNB4):​c.48T>C​(p.Asn16Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0349 in 1,601,692 control chromosomes in the GnomAD database, including 1,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (127 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1068 hom.)
• Consequence: GNB4 NM_021629.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.655
• Publications: 8 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 3-179426153-A-G is Benign according to our data. Variant chr3-179426153-A-G is described in ClinVar as Benign. ClinVar VariationId is 414883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.655 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB4	NM_021629.4	MANE Select	c.48T>C	p.Asn16Asn	synonymous	Exon 2 of 10	NP_067642.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB4	ENST00000232564.8	TSL:1 MANE Select	c.48T>C	p.Asn16Asn	synonymous	Exon 2 of 10	ENSP00000232564.3
	GNB4	ENST00000466899.6	TSL:1	c.48T>C	p.Asn16Asn	synonymous	Exon 1 of 8	ENSP00000420066.2
	GNB4	ENST00000674862.1		c.48T>C	p.Asn16Asn	synonymous	Exon 2 of 10	ENSP00000502628.1

Frequencies

GnomAD3 genomes AF: 0.0348 AC: 5302 AN: 152230 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0838

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0621

GnomAD2 exomes AF: 0.0333 AC: 7948 AN: 238918 AF XY: 0.0343

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.0306

Gnomad ASJ exome AF: 0.0773

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0561

GnomAD4 exome AF: 0.0349 AC: 50648 AN: 1449344 Hom.: 1068 Cov.: 29 AF XY: 0.0349 AC XY: 25171 AN XY: 720798

African (AFR) AF: 0.0266 AC: 868 AN: 32624

American (AMR) AF: 0.0328 AC: 1331 AN: 40536

Ashkenazi Jewish (ASJ) AF: 0.0769 AC: 1982 AN: 25776

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39532

South Asian (SAS) AF: 0.0209 AC: 1734 AN: 83054

European-Finnish (FIN) AF: 0.0225 AC: 1198 AN: 53316

Middle Eastern (MID) AF: 0.136 AC: 777 AN: 5732

European-Non Finnish (NFE) AF: 0.0363 AC: 40279 AN: 1108796

Other (OTH) AF: 0.0413 AC: 2476 AN: 59978

GnomAD4 genome AF: 0.0348 AC: 5303 AN: 152348 Hom.: 127 Cov.: 32 AF XY: 0.0340 AC XY: 2531 AN XY: 74504

African (AFR) AF: 0.0266 AC: 1106 AN: 41574

American (AMR) AF: 0.0406 AC: 621 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0838 AC: 291 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.0203 AC: 98 AN: 4834

European-Finnish (FIN) AF: 0.0200 AC: 213 AN: 10624

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.0393 AC: 2674 AN: 68030

Other (OTH) AF: 0.0615 AC: 130 AN: 2114

Alfa AF: 0.0399 Hom.: 380

Bravo AF: 0.0365

Asia WGS AF: 0.0120 AC: 40 AN: 3474

EpiCase AF: 0.0495

EpiControl AF: 0.0504

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease dominant intermediate F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.6
DANN	Benign	0.63
PhyloP100		0.66
PromoterAI		0.032	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1078749; hg19: chr3-179143941;