Genetic Variant GNG4:p.Arg50Gln (chr1-235552188-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001098722.2(GNG4):c.149G>A(p.Arg50Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,613,724 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 2 hom. )

Consequence

GNG4
NM_001098722.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.24

Publications

5 publications found

Variant links:

Genes affected

GNG4 (HGNC:4407): (G protein subunit gamma 4) Predicted to enable G-protein beta-subunit binding activity. Involved in negative regulation of cell growth. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

GNG4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.022912562).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098722.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNG4	NM_001098722.2	MANE Select	c.149G>A	p.Arg50Gln	missense	Exon 4 of 4	NP_001092192.1	P50150
GNG4	NM_001098721.2		c.149G>A	p.Arg50Gln	missense	Exon 4 of 4	NP_001092191.1	B1APZ0
GNG4	NM_004485.4		c.149G>A	p.Arg50Gln	missense	Exon 3 of 3	NP_004476.1	P50150

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNG4	ENST00000391854.7	TSL:1 MANE Select	c.149G>A	p.Arg50Gln	missense	Exon 4 of 4	ENSP00000375727.2	P50150
GNG4	ENST00000366597.5	TSL:1	c.149G>A	p.Arg50Gln	missense	Exon 3 of 3	ENSP00000355556.1	P50150
GNG4	ENST00000366598.8	TSL:1	c.149G>A	p.Arg50Gln	missense	Exon 3 of 3	ENSP00000355557.4	P50150

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000589

AC:

148

AN:

251124

AF XY:

0.000582

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00116

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000627

AC:

916

AN:

1461414

Hom.:

Cov.:

AF XY:

0.000641

AC XY:

466

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33474

American (AMR)

AF:

0.000134

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000344

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000771

AC:

857

AN:

1111616

Other (OTH)

AF:

0.000513

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<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:

0.000735

AC:

112

AN:

152310

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41578

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00140

AC:

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00106

Hom.:

Bravo

AF:

0.000661

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000667

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

Eigen

Benign

0.014

Eigen_PC

Benign

0.045

FATHMM_MKL

Benign

0.72

M_CAP

Benign

0.0096

MetaRNN

Benign

0.023

MetaSVM

Benign

-1.1

PhyloP100

2.2

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.2

REVEL

Benign

0.047

Sift

Benign

0.61

Sift4G

Benign

0.69

Polyphen

0.75

Vest4

0.15

MVP

0.70

MPC

0.33

ClinPred

0.027

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.088

gMVP

0.61

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over