3-179401322-GAAAAA-GAAAA

Variant names:

• chr3-179401322-GA-G
• rs764075662
• NM_021629.4:c.917-4delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_021629.4(GNB4):​c.917-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000046 in 1,586,640 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: GNB4 NM_021629.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.106
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 3-179401322-GA-G is Benign according to our data. Variant chr3-179401322-GA-G is described in ClinVar as Benign. ClinVar VariationId is 540921.Status of the report is criteria_provided_single_submitter, 1 stars.

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.917-4delT		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.917-4delT		splice_region intron	N/A	ENSP00000232564.3	Q9HAV0
	GNB4	ENST00000466899.6	TSL:1	c.700-4delT		splice_region intron	N/A	ENSP00000420066.2	H7C5J5
	GNB4	ENST00000674862.1		c.917-4delT		splice_region intron	N/A	ENSP00000502628.1	Q9HAV0

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150828 Hom.: 0 Cov.: 33

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000952 AC: 21 AN: 220670 AF XY: 0.0000669

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000364

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.000253

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000390

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000501 AC: 72 AN: 1435812 Hom.: 0 Cov.: 28 AF XY: 0.0000476 AC XY: 34 AN XY: 714184

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000620 AC: 2 AN: 32282

American (AMR) AF: 0.000265 AC: 11 AN: 41542

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25424

East Asian (EAS) AF: 0.000179 AC: 7 AN: 39110

South Asian (SAS) AF: 0.0000724 AC: 6 AN: 82862

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.0000374 AC: 41 AN: 1096884

Other (OTH) AF: 0.0000507 AC: 3 AN: 59162

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000663 AC: 1 AN: 150828 Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 1 AN XY: 73568

African (AFR) AF: 0.00 AC: 0 AN: 41000

American (AMR) AF: 0.00 AC: 0 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67736

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Benign

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
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs764075662;

hg19: chr3-179119110;

COSMIC: COSV51708992;

COSMIC: COSV51708992;