Genetic Variant GNG5:p.His45Arg (chr1-84501918-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_005274.3(GNG5):c.134A>G(p.His45Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,605,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

GNG5
NM_005274.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

Publications

2 publications found

Variant links:

Genes affected

GNG5 (HGNC:4408): (G protein subunit gamma 5) G proteins are trimeric (alpha-beta-gamma) membrane-associated proteins that regulate flow of information from cell surface receptors to a variety of internal metabolic effectors. Interaction of a G protein with its activated receptor promotes exchange of GTP for GDP that is bound to the alpha subunit. The alpha-GTP complex dissociates from the beta-gamma heterodimer so that the subunits, in turn, may interact with and regulate effector molecules (Gilman, 1987 [PubMed 3113327]; summary by Ahmad et al., 1995) [PubMed 7606925].[supplied by OMIM, Nov 2010]

GNG5 links:

ENSG00000285851 (HGNC:):

ENSG00000285851 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0996353).

BS2

High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005274.3. 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
	GNG5	NM_005274.3	MANE Select	c.134A>G	p.His45Arg	missense	Exon 3 of 4	NP_005265.1	P63218

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNG5	ENST00000370645.9	TSL:2 MANE Select	c.134A>G	p.His45Arg	missense	Exon 3 of 4	ENSP00000359679.4	P63218
GNG5	ENST00000370641.3	TSL:1	c.134A>G	p.His45Arg	missense	Exon 2 of 3	ENSP00000359675.3	P63218
GNG5	ENST00000686161.1		c.134A>G	p.His45Arg	missense	Exon 2 of 2	ENSP00000510172.1	P63218

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152130

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:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251358

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1453184

Hom.:

Cov.:

AF XY:

0.00000829

AC XY:

AN XY:

723540

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33286

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.000328

AC:

AN:

39638

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1104124

Other (OTH)

AF:

0.00

AC:

AN:

60094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41540

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00135

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.00

Hom.:

Bravo

AF:

0.0000302

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

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.028

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.59

M_CAP

Benign

0.0098

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.1

PhyloP100

7.7

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.39

REVEL

Benign

0.13

Sift

Benign

0.16

Sift4G

Benign

0.53

Polyphen

0.0010

Vest4

0.33

MutPred

0.27

Gain of disorder (P = 0.0404)

MVP

0.36

MPC

0.55

ClinPred

0.69

GERP RS

5.6

Varity_R

0.16

gMVP

0.40

Mutation Taster

=67/33

polymorphism

(source)

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

Publications

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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