rs1362650

Variant names:

• chr3-179419485-A-G
• rs1362650
• NM_021629.4:c.117T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-179419485-A-G
• chr3-179419485-A-T

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.117T>C​(p.Ser39Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,601,116 control chromosomes in the GnomAD database, including 177,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S39S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.47 (16872 hom., cov: 32)
  • Exomes 𝑓: 0.47 (160903 hom.)
• Consequence: GNB4 NM_021629.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.67
• Publications: 29 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.87).
• BP6: Variant 3-179419485-A-G is Benign according to our data. Variant chr3-179419485-A-G is described in ClinVar as Benign. ClinVar VariationId is 261427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.67 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.507 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB4	NM_021629.4	MANE Select	c.117T>C	p.Ser39Ser	synonymous	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.117T>C	p.Ser39Ser	synonymous	Exon 4 of 10	ENSP00000232564.3	Q9HAV0
	GNB4	ENST00000466899.6	TSL:1	c.117T>C	p.Ser39Ser	synonymous	Exon 3 of 8	ENSP00000420066.2	H7C5J5
	GNB4	ENST00000674862.1		c.117T>C	p.Ser39Ser	synonymous	Exon 4 of 10	ENSP00000502628.1	Q9HAV0

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71358 AN: 151818 Hom.: 16851 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.436

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.471

GnomAD2 exomes AF: 0.476 AC: 119489 AN: 251164 AF XY: 0.478

Gnomad AFR exome AF: 0.448

Gnomad AMR exome AF: 0.503

Gnomad ASJ exome AF: 0.475

Gnomad EAS exome AF: 0.429

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.464

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.469 AC: 679732 AN: 1449180 Hom.: 160903 Cov.: 29 AF XY: 0.472 AC XY: 340343 AN XY: 721738

African (AFR) AF: 0.445 AC: 14761 AN: 33206

American (AMR) AF: 0.504 AC: 22500 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 12543 AN: 26032

East Asian (EAS) AF: 0.464 AC: 18374 AN: 39608

South Asian (SAS) AF: 0.515 AC: 44233 AN: 85938

European-Finnish (FIN) AF: 0.505 AC: 26981 AN: 53390

Middle Eastern (MID) AF: 0.422 AC: 2428 AN: 5750

European-Non Finnish (NFE) AF: 0.463 AC: 509789 AN: 1100660

Other (OTH) AF: 0.469 AC: 28123 AN: 59948

GnomAD4 genome AF: 0.470 AC: 71404 AN: 151936 Hom.: 16872 Cov.: 32 AF XY: 0.471 AC XY: 34976 AN XY: 74242

African (AFR) AF: 0.451 AC: 18703 AN: 41426

American (AMR) AF: 0.516 AC: 7882 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1651 AN: 3468

East Asian (EAS) AF: 0.436 AC: 2250 AN: 5164

South Asian (SAS) AF: 0.509 AC: 2454 AN: 4820

European-Finnish (FIN) AF: 0.512 AC: 5391 AN: 10530

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.464 AC: 31539 AN: 67944

Other (OTH) AF: 0.476 AC: 1004 AN: 2108

Alfa AF: 0.466 Hom.: 26414

Bravo AF: 0.466

Asia WGS AF: 0.491 AC: 1703 AN: 3478

EpiCase AF: 0.469

EpiControl AF: 0.476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.4
DANN	Benign	0.55
PhyloP100		-2.7
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: rs1362650; hg19: chr3-179137273; COSMIC: COSV51708596; COSMIC: COSV51708596;