3-30728289-T-G

Variant names:

• chr3-30728289-T-G
• rs1695399599
• NM_207359.3:c.1519A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_207359.3(GADL1):​c.1519A>C​(p.Met507Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GADL1 NM_207359.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

Genes affected

GADL1 (HGNC:27949): (glutamate decarboxylase like 1) Predicted to enable aspartate 1-decarboxylase activity; pyridoxal phosphate binding activity; and sulfinoalanine decarboxylase activity. Predicted to be involved in carboxylic acid metabolic process. Predicted to be located in cytosol. [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
• BP4: Computational evidence support a benign effect (MetaRNN=0.13173008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GADL1	NM_207359.3	c.1519A>C	p.Met507Leu	missense_variant	Exon 15 of 15	ENST00000282538.10	NP_997242.2
GADL1	XM_017006297.2	c.1462A>C	p.Met488Leu	missense_variant	Exon 15 of 15		XP_016861786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GADL1	ENST00000282538.10	c.1519A>C	p.Met507Leu	missense_variant	Exon 15 of 15	5	NM_207359.3	ENSP00000282538.5
GADL1	ENST00000498387.1	n.576A>C		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461572 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727076

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1519A>C (p.M507L) alteration is located in exon 15 (coding exon 15) of the GADL1 gene. This alteration results from a A to C substitution at nucleotide position 1519, causing the methionine (M) at amino acid position 507 to be replaced by a leucine (L). 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	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.079
Sift	Benign	0.24	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.29
MutPred		0.48		Loss of loop (P = 0.0022);
MVP		0.030
MPC		0.0095
ClinPred		0.54	D
GERP RS		5.9
Varity_R		0.28
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs1695399599; hg19: chr3-30769781;