chr9-77794572-T-A

Variant names:

• chr9-77794572-T-A
• rs121913492
• NM_002072.5:c.626A>T
• GNAQ p.Gln209Leu

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_002072.5(GNAQ):​c.626A>T​(p.Gln209Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV005049541: "In support of this prediction, functional studies show increased activation of mitogen-activated protein kinase (MAPK) signaling pathways and associated downstream transcriptional programs leading to cellular transformation (Galeffi F et al., PMID:35635655" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q209P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNAQ NM_002072.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02
• Publications: 496 publications found

Genes affected

GNAQ (HGNC:4390): (G protein subunit alpha q) This locus encodes a guanine nucleotide-binding protein. The encoded protein, an alpha subunit in the Gq class, couples a seven-transmembrane domain receptor to activation of phospolipase C-beta. Mutations at this locus have been associated with problems in platelet activation and aggregation. A related pseudogene exists on chromosome 2.[provided by RefSeq, Nov 2010]

GNAQ Gene-Disease associations (from GenCC):

• congenital hemangioma

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Sturge-Weber syndrome

  Inheritance: AD Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005049541: "In support of this prediction, functional studies show increased activation of mitogen-activated protein kinase (MAPK) signaling pathways and associated downstream transcriptional programs leading to cellular transformation (Galeffi F et al., PMID: 35635655; Thomas AC et al., PMID: 26778290; Van Raamsdonk CD et al., PMID: 19078957)."
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-77794571-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1172602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.6575 (above the threshold of 3.09). Trascript score misZ: 2.6566 (below the threshold of 3.09). GenCC associations: The gene is linked to Sturge-Weber syndrome, congenital hemangioma.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 9-77794572-T-A is Pathogenic according to our data. Variant chr9-77794572-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 375955.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002072.5. 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
	GNAQ	NM_002072.5	MANE Select	c.626A>T	p.Gln209Leu	missense	Exon 5 of 7	NP_002063.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAQ	ENST00000286548.9	TSL:1 MANE Select	c.626A>T	p.Gln209Leu	missense	Exon 5 of 7	ENSP00000286548.4	P50148
	GNAQ	ENST00000857199.1		c.701A>T	p.Gln234Leu	missense	Exon 6 of 8	ENSP00000527258.1
	GNAQ	ENST00000915940.1		c.626A>T	p.Gln209Leu	missense	Exon 6 of 8	ENSP00000585999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Sturge-Weber syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.92
gMVP		0.99
Mutation Taster		=16/84	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121913492;

hg19: chr9-80409488;

COSMIC: COSV54105914;

COSMIC: COSV54105914;