3-179401322-GAAAAA-GAAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_021629.4(GNB4):c.917-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000401 in 1,582,718 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

GNB4
NM_021629.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.106

Publications

0 publications found

Variant links:

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

GNB4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP6

Variant 3-179401322-G-GA is Benign according to our data. Variant chr3-179401322-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1161907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNB4	NM_021629.4 link	c.917-4dupT		splice_region_variant, intron_variant	Intron 9 of 9	ENST00000232564.8	NP_067642.1	Q9HAV0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB4	ENST00000232564.8 link	c.917-4_917-3insT		splice_region_variant, intron_variant	Intron 9 of 9	1	NM_021629.4	ENSP00000232564.3		Q9HAV0

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150824

Hom.:

Cov.:

show subpopulations

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:

0.000548

AC:

121

AN:

220670

AF XY:

0.000577

show subpopulations

Gnomad AFR exome

AF:

0.000414

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.000229

Gnomad EAS exome

AF:

0.000632

Gnomad FIN exome

AF:

0.0000479

Gnomad NFE exome

AF:

0.000361

Gnomad OTH exome

AF:

0.000393

GnomAD4 exome

AF:

0.000443

AC:

634

AN:

1431894

Hom.:

Cov.:

AF XY:

0.000437

AC XY:

311

AN XY:

712254

show subpopulations

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

African (AFR)

AF:

0.000342

AC:

AN:

32172

American (AMR)

AF:

0.000772

AC:

AN:

41438

Ashkenazi Jewish (ASJ)

AF:

0.000394

AC:

AN:

25358

East Asian (EAS)

AF:

0.000256

AC:

AN:

39016

South Asian (SAS)

AF:

0.000727

AC:

AN:

82498

European-Finnish (FIN)

AF:

0.000208

AC:

AN:

52788

Middle Eastern (MID)

AF:

0.000707

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

0.000431

AC:

471

AN:

1093960

Other (OTH)

AF:

0.000424

AC:

AN:

59010

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.243

Heterozygous variant carriers

102

203

305

406

508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150824

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41000

American (AMR)

AF:

0.00

AC:

AN:

15148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67734

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00213

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Oct 27, 2021

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GNB4: BP4, BS1 -

Charcot-Marie-Tooth disease dominant intermediate F

Benign:1

Jun 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GNB4-related disorder

Benign:1

Jul 12, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.11

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over