chr7-2731264-C-A

Variant names:

• chr7-2731264-C-A
• rs560123937
• NM_007353.3:c.1063G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_007353.3(GNA12):​c.1063G>T​(p.Asp355Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GNA12 NM_007353.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04
• Publications: 3 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007353.3. 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
	GNA12	NM_007353.3	MANE Select	c.1063G>T	p.Asp355Tyr	missense	Exon 4 of 4	NP_031379.2
	GNA12	NM_001293092.2		c.1012G>T	p.Asp338Tyr	missense	Exon 3 of 3	NP_001280021.1
	GNA12	NM_001282441.2		c.886G>T	p.Asp296Tyr	missense	Exon 5 of 5	NP_001269370.1	Q03113-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNA12	ENST00000275364.8	TSL:1 MANE Select	c.1063G>T	p.Asp355Tyr	missense	Exon 4 of 4	ENSP00000275364.3	Q03113-1
	AMZ1	ENST00000489665.1	TSL:1	n.550+21448C>A		intron	N/A
	GNA12	ENST00000954395.1		c.1141G>T	p.Asp381Tyr	missense	Exon 5 of 5	ENSP00000624454.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 149076 Hom.: 0 Cov.: 31

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251344 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461610 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111888

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 149076 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 72776

African (AFR) AF: 0.00 AC: 0 AN: 40348

American (AMR) AF: 0.00 AC: 0 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 5054

South Asian (SAS) AF: 0.00 AC: 0 AN: 4604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66874

Other (OTH) AF: 0.00 AC: 0 AN: 2024

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		4.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.94		Gain of catalytic residue at I354 (P = 0.0202)
MVP		0.97
MPC		1.8
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.96
Mutation Taster		=23/77	disease causing

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: rs560123937; hg19: chr7-2770898;