rs1554685903

Positions:

• chr9-77429016-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_004297.4(GNA14):​c.614A>T​(p.Gln205Leu) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNA14 NM_004297.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.02

Genes affected

GNA14 (HGNC:4382): (G protein subunit alpha 14) This gene encodes a member of the guanine nucleotide-binding, or G protein family. G proteins are heterotrimers consisting of alpha, beta and gamma subunits. The encoded protein is a member of the alpha family of G proteins, more specifically the alpha q subfamily of G proteins. The encoded protein may play a role in pertussis-toxin resistant activation of phospholipase C-beta and its downstream effectors.[provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 9-77429016-T-A is Pathogenic according to our data. Variant chr9-77429016-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 548667.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNA14	NM_004297.4	c.614A>T	p.Gln205Leu	missense_variant	5/7	ENST00000341700.7	NP_004288.1
GNA14	XM_047424110.1	c.260A>T	p.Gln87Leu	missense_variant	4/6		XP_047280066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNA14	ENST00000341700.7	c.614A>T	p.Gln205Leu	missense_variant	5/7	1	NM_004297.4	ENSP00000365807	P1
GNA14	ENST00000464095.1	n.389A>T		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

May 12, 2021

This variant has previously been reported in several unrelated individuals with GLUT-1 negative vascular tumors, including kaposiform hemangioendothelioma, tufted angioma, and lobular capillary hemangioma (PMID: 27476652, PMID: 31707589). Functional studies have demonstrated that the substitution of glutamine with leucine at position 205 leads to deregulated MAPK activation (PMID: 27476652). -

Pyogenic granuloma;C1367420:Kaposiform hemangioendothelioma;CN252650:Congenital tufted angioma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Jul 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.88		Loss of disorder (P = 0.0157);
MVP		0.90
MPC		0.58
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.70
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs1554685903; hg19: chr9-80043932;