7-2762657-T-C

Variant names:

• chr7-2762657-T-C
• rs10487576
• NM_007353.3:c.526-29156A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001282440.1(GNA12):​c.232A>G​(p.Ile78Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,598,710 control chromosomes in the GnomAD database, including 203 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.021 (74 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (129 hom.)
• Consequence: GNA12 NM_001282440.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 2 publications found

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]

AMZ1 (HGNC:22231): (archaelysin family metallopeptidase 1) Predicted to enable metal ion binding activity and metallopeptidase activity. Predicted to be involved in proteolysis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002007693).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0537 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282440.1. 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
	GNA12	NM_007353.3	MANE Select	c.526-29156A>G		intron	N/A	NP_031379.2
	GNA12	NM_001282440.1		c.232A>G	p.Ile78Val	missense	Exon 1 of 3	NP_001269369.1
	GNA12	NM_001293092.2		c.526-30907A>G		intron	N/A	NP_001280021.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNA12	ENST00000275364.8	TSL:1 MANE Select	c.526-29156A>G		intron	N/A	ENSP00000275364.3
	AMZ1	ENST00000489665.1	TSL:1	n.551-2055T>C		intron	N/A
	GNA12	ENST00000407653.1	TSL:2	c.232A>G	p.Ile78Val	missense	Exon 1 of 3	ENSP00000386054.1

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3232 AN: 152112 Hom.: 74 Cov.: 33

Gnomad AFR AF: 0.0555

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.00756

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0105 AC: 2349 AN: 223436 AF XY: 0.0102

Gnomad AFR exome AF: 0.0588

Gnomad AMR exome AF: 0.00891

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.000180

Gnomad FIN exome AF: 0.000768

Gnomad NFE exome AF: 0.00903

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.00892 AC: 12908 AN: 1446480 Hom.: 129 Cov.: 30 AF XY: 0.00874 AC XY: 6276 AN XY: 718240

African (AFR) AF: 0.0571 AC: 1891 AN: 33128

American (AMR) AF: 0.0107 AC: 455 AN: 42672

Ashkenazi Jewish (ASJ) AF: 0.0178 AC: 460 AN: 25886

East Asian (EAS) AF: 0.0000512 AC: 2 AN: 39026

South Asian (SAS) AF: 0.00495 AC: 411 AN: 83022

European-Finnish (FIN) AF: 0.00102 AC: 53 AN: 51882

Middle Eastern (MID) AF: 0.0368 AC: 212 AN: 5756

European-Non Finnish (NFE) AF: 0.00783 AC: 8649 AN: 1105214

Other (OTH) AF: 0.0129 AC: 775 AN: 59894

GnomAD4 genome AF: 0.0213 AC: 3239 AN: 152230 Hom.: 74 Cov.: 33 AF XY: 0.0209 AC XY: 1559 AN XY: 74448

African (AFR) AF: 0.0556 AC: 2310 AN: 41524

American (AMR) AF: 0.0158 AC: 241 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4822

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10604

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.00753 AC: 512 AN: 68024

Other (OTH) AF: 0.0279 AC: 59 AN: 2112

Alfa AF: 0.0228 Hom.: 24

Bravo AF: 0.0254

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.0514 AC: 90

ESP6500EA AF: 0.00879 AC: 35

ExAC AF: 0.0107 AC: 1255

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.20
DANN	Benign	0.63
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.83	T
PhyloP100		-1.5
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.070
Sift	Uncertain	0.012	D
Sift4G	Benign	0.34	T
Vest4		0.021
ClinPred		0.0029	T
GERP RS		-3.2
PromoterAI		0.052	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10487576; hg19: chr7-2802291; COSMIC: COSV107295091; COSMIC: COSV107295091;