3-30800894-T-A

Variant names:

• chr3-30800894-T-A
• rs771004854
• NM_207359.3:c.1245A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_207359.3(GADL1):​c.1245A>T​(p.Leu415Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GADL1 NM_207359.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.636

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31396767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GADL1	NM_207359.3	c.1245A>T	p.Leu415Phe	missense_variant	Exon 12 of 15	ENST00000282538.10	NP_997242.2
GADL1	XM_017006297.2	c.1188A>T	p.Leu396Phe	missense_variant	Exon 12 of 15		XP_016861786.1
GADL1	XM_047448071.1	c.1245A>T	p.Leu415Phe	missense_variant	Exon 12 of 14		XP_047304027.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GADL1	ENST00000282538.10	c.1245A>T	p.Leu415Phe	missense_variant	Exon 12 of 15	5	NM_207359.3	ENSP00000282538.5
GADL1	ENST00000454381.3	c.1245A>T	p.Leu415Phe	missense_variant	Exon 12 of 12	1		ENSP00000427059.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454916 Hom.: 0 Cov.: 34 AF XY: 0.00000414 AC XY: 3 AN XY: 724256

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1245A>T (p.L415F) alteration is located in exon 12 (coding exon 12) of the GADL1 gene. This alteration results from a A to T substitution at nucleotide position 1245, causing the leucine (L) at amino acid position 415 to be replaced by a phenylalanine (F). 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	0.15
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.28	T;T
Polyphen		0.97	D;.
Vest4		0.62
MutPred		0.74		Gain of catalytic residue at L415 (P = 0.1306);Gain of catalytic residue at L415 (P = 0.1306);
MVP		0.18
MPC		0.013
ClinPred		0.77	D
GERP RS		3.1
Varity_R		0.081
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs771004854; hg19: chr3-30842386;