3-179420934-TA-TAA

Variant names:

• chr3-179420934-T-TA
• rs112500963
• NM_021629.4:c.58-8dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_021629.4(GNB4):​c.58-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,550,452 control chromosomes in the GnomAD database, including 116 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (45 hom.)
• Consequence: GNB4 NM_021629.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.42
• 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: Orphanet, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 3-179420934-T-TA is Benign according to our data. Variant chr3-179420934-T-TA is described in ClinVar as Benign. ClinVar VariationId is 414881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0525 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.58-8dupT		splice_region intron	N/A	NP_067642.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB4	ENST00000232564.8	TSL:1 MANE Select	c.58-8_58-7insT		splice_region intron	N/A	ENSP00000232564.3
	GNB4	ENST00000466899.6	TSL:1	c.58-8_58-7insT		splice_region intron	N/A	ENSP00000420066.2
	GNB4	ENST00000674862.1		c.58-8_58-7insT		splice_region intron	N/A	ENSP00000502628.1

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2359 AN: 152094 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.0543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00372 AC: 897 AN: 241200 AF XY: 0.00282

Gnomad AFR exome AF: 0.0488

Gnomad AMR exome AF: 0.00251

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000315

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.00155 AC: 2168 AN: 1398240 Hom.: 45 Cov.: 22 AF XY: 0.00138 AC XY: 965 AN XY: 699108

African (AFR) AF: 0.0520 AC: 1645 AN: 31630

American (AMR) AF: 0.00320 AC: 137 AN: 42842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25676

East Asian (EAS) AF: 0.0000770 AC: 3 AN: 38980

South Asian (SAS) AF: 0.000205 AC: 17 AN: 82954

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53300

Middle Eastern (MID) AF: 0.00195 AC: 11 AN: 5638

European-Non Finnish (NFE) AF: 0.000111 AC: 118 AN: 1058984

Other (OTH) AF: 0.00404 AC: 235 AN: 58236

GnomAD4 genome AF: 0.0156 AC: 2371 AN: 152212 Hom.: 71 Cov.: 32 AF XY: 0.0156 AC XY: 1160 AN XY: 74438

African (AFR) AF: 0.0544 AC: 2260 AN: 41544

American (AMR) AF: 0.00451 AC: 69 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67984

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.00701 Hom.: 3

Bravo AF: 0.0172

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Charcot-Marie-Tooth disease dominant intermediate F (2)
-	-	1	GNB4-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112500963; hg19: chr3-179138722;