7-2843920-T-C

Position:

• chr7-2843920-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PP3_Moderate BS2

The NM_007353.3(GNA12):​c.242A>G​(p.His81Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000348 in 1,438,196 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: not found (cov: 28)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: GNA12 NM_007353.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.52

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNA12	NM_007353.3	c.242A>G	p.His81Arg	missense_variant	1/4	ENST00000275364.8	NP_031379.2
GNA12	NM_001293092.2	c.242A>G	p.His81Arg	missense_variant	1/3		NP_001280021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNA12	ENST00000275364.8	c.242A>G	p.His81Arg	missense_variant	1/4	1	NM_007353.3	ENSP00000275364.3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1438196 Hom.: 0 Cov.: 31 AF XY: 0.00000559 AC XY: 4 AN XY: 714964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 28, 2024

The c.242A>G (p.H81R) alteration is located in exon 1 (coding exon 1) of the GNA12 gene. This alteration results from a A to G substitution at nucleotide position 242, causing the histidine (H) at amino acid position 81 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.76	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	4.1	H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.90	P
Vest4		0.38
MutPred		0.86		Gain of sheet (P = 0.0125);
MVP		0.91
MPC		1.5
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.94
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-2883554;