chr3-179405409-A-G

Variant names:

• chr3-179405409-A-G
• rs199620294
• NM_021629.4:c.700-3T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_021629.4(GNB4):​c.700-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,596,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: GNB4 NM_021629.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006166
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.559
• Publications: 0 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

ENSG00000272699 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS2: High AC in GnomAdExome4 at 14 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.700-3T>C		splice_region intron	N/A	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.700-3T>C		splice_region intron	N/A	ENSP00000232564.3	Q9HAV0
	GNB4	ENST00000466899.6	TSL:1	c.700-4090T>C		intron	N/A	ENSP00000420066.2	H7C5J5
	GNB4	ENST00000674862.1		c.700-3T>C		splice_region intron	N/A	ENSP00000502628.1	Q9HAV0

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000970 AC: 14 AN: 1443890 Hom.: 0 Cov.: 26 AF XY: 0.0000111 AC XY: 8 AN XY: 718116

African (AFR) AF: 0.00 AC: 0 AN: 32904

American (AMR) AF: 0.00 AC: 0 AN: 43898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 85332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1097778

Other (OTH) AF: 0.0000167 AC: 1 AN: 59718

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

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
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.6
DANN	Benign	0.65
PhyloP100		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000062
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.060		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: rs199620294; hg19: chr3-179123197;