9-127318064-G-A

Position:

• chr9-127318064-G-A

Variant summary

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

The NM_032293.5(GARNL3):​c.440G>A​(p.Gly147Asp) variant causes a missense, splice region 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. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GARNL3 NM_032293.5 missense, splice_region
• Scores: Splicing: ADA: 0.9964
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.45

Genes affected

GARNL3 (HGNC:25425): (GTPase activating Rap/RanGAP domain like 3) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARNL3	NM_032293.5	c.440G>A	p.Gly147Asp	missense_variant, splice_region_variant	5/28	ENST00000373387.9	NP_115669.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARNL3	ENST00000373387.9	c.440G>A	p.Gly147Asp	missense_variant, splice_region_variant	5/28	1	NM_032293.5	ENSP00000362485	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

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

Oct 27, 2022

The c.440G>A (p.G147D) alteration is located in exon 5 (coding exon 5) of the GARNL3 gene. This alteration results from a G to A substitution at nucleotide position 440, causing the glycine (G) at amino acid position 147 to be replaced by an aspartic acid (D). 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	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.6	.;.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.029	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.94, 0.93
MutPred		0.57		.;.;.;Gain of sheet (P = 0.0061);
MVP		0.86
MPC		1.4
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.85
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.72
SpliceAI score (max)		0.030		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: chr9-130080343;