16-19504903-T-A

Position:

• chr16-19504903-T-A

Variant summary

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

The ENST00000353258.8(GDE1):​c.826A>T​(p.Met276Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,459,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000082 (0 hom.)
• Consequence: GDE1 ENST00000353258.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66

Genes affected

GDE1 (HGNC:29644): (glycerophosphodiester phosphodiesterase 1) Predicted to enable glycerophosphodiester phosphodiesterase activity; glycerophosphoinositol glycerophosphodiesterase activity; and lysophospholipase activity. Predicted to be involved in N-acylethanolamine metabolic process; ethanolamine metabolic process; and phospholipid metabolic process. Predicted to be located in plasma membrane. [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=0.09804034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDE1	NM_016641.4	c.826A>T	p.Met276Leu	missense_variant	5/6	ENST00000353258.8	NP_057725.1
GDE1	NM_001324067.2	c.733A>T	p.Met245Leu	missense_variant	4/5		NP_001310996.1
GDE1	NM_001324066.2	c.496A>T	p.Met166Leu	missense_variant	5/6		NP_001310995.1
GDE1	NR_136689.2	n.992A>T		non_coding_transcript_exon_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDE1	ENST00000353258.8	c.826A>T	p.Met276Leu	missense_variant	5/6	1	NM_016641.4	ENSP00000261386	P1
GDE1	ENST00000564172.1	c.*495A>T		3_prime_UTR_variant, NMD_transcript_variant	5/6	1		ENSP00000457431
GDE1	ENST00000569899.5	c.*186A>T		3_prime_UTR_variant	4/4	4		ENSP00000456295
GDE1	ENST00000563645.1	n.230A>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459578 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726136

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: 0.0000108

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2021

The c.826A>T (p.M276L) alteration is located in exon 5 (coding exon 5) of the GDE1 gene. This alteration results from a A to T substitution at nucleotide position 826, causing the methionine (M) at amino acid position 276 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	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Benign	0.81
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.10	N
MutationTaster	Benign	0.89	D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.016
Sift	Benign	1.0	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.31
MutPred		0.56		Gain of catalytic residue at M276 (P = 0.0262);
MVP		0.19
MPC		0.18
ClinPred		0.11	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1309765774; hg19: chr16-19516225;