chr9-77728671-GA-G

Variant names:

• chr9-77728671-GA-G
• rs5898555
• NM_002072.5:c.736-5delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_002072.5(GNAQ):​c.736-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,295,286 control chromosomes in the GnomAD database, including 110 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (102 hom., cov: 0)
  • Exomes 𝑓: 0.031 (8 hom.)
• Consequence: GNAQ NM_002072.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.572
• Publications: 5 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, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-77728671-GA-G is Benign according to our data. Variant chr9-77728671-GA-G is described in ClinVar as Benign. ClinVar VariationId is 776427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0603 is higher than 0.05.

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.736-5delT		splice_region intron	N/A	NP_002063.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNAQ	ENST00000286548.9	TSL:1 MANE Select	c.736-5delT		splice_region intron	N/A	ENSP00000286548.4	P50148
	GNAQ	ENST00000857199.1		c.811-5delT		splice_region intron	N/A	ENSP00000527258.1
	GNAQ	ENST00000915940.1		c.736-5delT		splice_region intron	N/A	ENSP00000585999.1

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2659 AN: 145548 Hom.: 102 Cov.: 0

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00770

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.00304

Gnomad SAS AF: 0.000647

Gnomad FIN AF: 0.00138

Gnomad MID AF: 0.00662

Gnomad NFE AF: 0.000511

Gnomad OTH AF: 0.0131

GnomAD2 exomes AF: 0.0423 AC: 7232 AN: 170990 AF XY: 0.0395

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.0412

Gnomad ASJ exome AF: 0.0380

Gnomad EAS exome AF: 0.0916

Gnomad FIN exome AF: 0.0374

Gnomad NFE exome AF: 0.0244

Gnomad OTH exome AF: 0.0379

GnomAD4 exome AF: 0.0307 AC: 35312 AN: 1149670 Hom.: 8 Cov.: 22 AF XY: 0.0311 AC XY: 17934 AN XY: 576428

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.111 AC: 2844 AN: 25732

American (AMR) AF: 0.0396 AC: 1122 AN: 28298

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 713 AN: 20622

East Asian (EAS) AF: 0.0668 AC: 2272 AN: 34030

South Asian (SAS) AF: 0.0436 AC: 2972 AN: 68132

European-Finnish (FIN) AF: 0.0354 AC: 1468 AN: 41436

Middle Eastern (MID) AF: 0.0299 AC: 132 AN: 4414

European-Non Finnish (NFE) AF: 0.0251 AC: 22045 AN: 878496

Other (OTH) AF: 0.0360 AC: 1744 AN: 48510

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0184 AC: 2673 AN: 145616 Hom.: 102 Cov.: 0 AF XY: 0.0176 AC XY: 1240 AN XY: 70570

African (AFR) AF: 0.0623 AC: 2467 AN: 39598

American (AMR) AF: 0.00769 AC: 113 AN: 14688

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3420

East Asian (EAS) AF: 0.00304 AC: 15 AN: 4930

South Asian (SAS) AF: 0.000650 AC: 3 AN: 4614

European-Finnish (FIN) AF: 0.00138 AC: 12 AN: 8710

Middle Eastern (MID) AF: 0.00725 AC: 2 AN: 276

European-Non Finnish (NFE) AF: 0.000512 AC: 34 AN: 66466

Other (OTH) AF: 0.0129 AC: 26 AN: 2008

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.57
Mutation Taster		=99/1	polymorphism

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: rs5898555; hg19: chr9-80343587; COSMIC: COSV54106660;