Genetic Variant GNA12:c.310-19218G>A (chr7-2814361-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001282441.2(GNA12):c.83G>A(p.Arg28Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 1,603,128 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0059 ( 6 hom., cov: 31)

Exomes 𝑓: 0.0079 ( 70 hom. )

Consequence

GNA12
NM_001282441.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.109

Publications

2 publications found

Variant links:

Genes affected

GNA12 (HGNC:4380): (G protein subunit alpha 12) Predicted to enable D5 dopamine receptor binding activity; G-protein beta/gamma-subunit complex binding activity; and GTPase activity. Involved in regulation of TOR signaling and regulation of proteasomal ubiquitin-dependent protein catabolic process. Located in focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

GNA12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004283428).

BP6

Variant 7-2814361-C-T is Benign according to our data. Variant chr7-2814361-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2657237.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00793 (11507/1451118) while in subpopulation MID AF = 0.0254 (146/5744). AF 95% confidence interval is 0.0221. There are 70 homozygotes in GnomAdExome4. There are 5671 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High AC in GnomAd4 at 904 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282441.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNA12	NM_007353.3	MANE Select	c.310-19218G>A		intron	N/A	NP_031379.2
GNA12	NM_001282441.2		c.83G>A	p.Arg28Gln	missense	Exon 2 of 5	NP_001269370.1	Q03113-2
GNA12	NM_001293092.2		c.310-19218G>A		intron	N/A	NP_001280021.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GNA12	ENST00000275364.8	TSL:1 MANE Select	c.310-19218G>A		intron	N/A	ENSP00000275364.3	Q03113-1
GNA12	ENST00000954395.1		c.338G>A	p.Arg113Gln	missense	Exon 2 of 5	ENSP00000624454.1
GNA12	ENST00000407904.7	TSL:2	c.83G>A	p.Arg28Gln	missense	Exon 2 of 5	ENSP00000385935.3	Q03113-2

Frequencies

GnomAD3 genomes

AF:

0.00594

AC:

902

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00617

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00374

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00956

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00607

AC:

1467

AN:

241542

AF XY:

0.00655

show subpopulations

Gnomad AFR exome

AF:

0.00133

Gnomad AMR exome

AF:

0.00366

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000975

Gnomad NFE exome

AF:

0.00998

Gnomad OTH exome

AF:

0.00686

GnomAD4 exome

AF:

0.00793

AC:

11507

AN:

1451118

Hom.:

Cov.:

AF XY:

0.00785

AC XY:

5671

AN XY:

722500

show subpopulations

African (AFR)

AF:

0.00192

AC:

AN:

33326

American (AMR)

AF:

0.00423

AC:

189

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

269

AN:

26092

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39670

South Asian (SAS)

AF:

0.00305

AC:

263

AN:

86114

European-Finnish (FIN)

AF:

0.000937

AC:

AN:

52290

Middle Eastern (MID)

AF:

0.0254

AC:

146

AN:

5744

European-Non Finnish (NFE)

AF:

0.00909

AC:

10025

AN:

1103138

Other (OTH)

AF:

0.00831

AC:

499

AN:

60038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

511

1022

1532

2043

2554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

376

752

1128

1504

1880

<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:

0.00595

AC:

904

AN:

152010

Hom.:

Cov.:

AF XY:

0.00583

AC XY:

433

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41460

American (AMR)

AF:

0.00616

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.00375

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00956

AC:

650

AN:

67992

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00806

Hom.:

Bravo

AF:

0.00640

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00171

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00639

AC:

741

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0114

EpiControl

AF:

0.0120

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0043

MetaSVM

Benign

-0.52

PhyloP100

-0.11

PROVEAN

Benign

1.2

REVEL

Benign

0.17

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.014

Vest4

0.12

MVP

0.47

ClinPred

0.0030

GERP RS

2.1

Mutation Taster

=100/0

polymorphism

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over