chr16-19507722-C-A

Position:

• chr16-19507722-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016641.4(GDE1):​c.601G>T​(p.Val201Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,584,382 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: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: GDE1 NM_016641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03771311).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDE1	NM_016641.4	c.601G>T	p.Val201Leu	missense_variant	4/6	ENST00000353258.8
GDE1	NM_001324066.2	c.271G>T	p.Val91Leu	missense_variant	4/6
GDE1	NM_001324067.2	c.544-2630G>T		intron_variant
GDE1	NR_136689.2	n.735G>T		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDE1	ENST00000353258.8	c.601G>T	p.Val201Leu	missense_variant	4/6	1	NM_016641.4	P1
GDE1	ENST00000564172.1	c.*270G>T		3_prime_UTR_variant, NMD_transcript_variant	4/6	1
GDE1	ENST00000569899.5	c.319G>T	p.Val107Leu	missense_variant	3/4	4
GDE1	ENST00000569773.1	c.271G>T	p.Val91Leu	missense_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000462 AC: 116 AN: 250874 Hom.: 0 AF XY: 0.000428 AC XY: 58 AN XY: 135598

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000957

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000644

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000455 AC: 652 AN: 1432158 Hom.: 0 Cov.: 25 AF XY: 0.000411 AC XY: 294 AN XY: 714558

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.000986

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000528

Gnomad4 OTH exome AF: 0.000539

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74374

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000647 Hom.: 0

Bravo AF: 0.000332

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000818

EpiControl AF: 0.000771

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

May 24, 2023

The c.601G>T (p.V201L) alteration is located in exon 4 (coding exon 4) of the GDE1 gene. This alteration results from a G to T substitution at nucleotide position 601, causing the valine (V) at amino acid position 201 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	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.83
DEOGEN2	Benign	0.027	T;.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.67	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N;.;N
REVEL	Benign	0.025
Sift	Benign	0.19	T;.;T
Sift4G	Benign	0.34	T;T;.
Polyphen		0.0030	B;.;.
Vest4		0.32
MutPred		0.62		Loss of catalytic residue at V201 (P = 0.1051);.;.;
MVP		0.095
MPC		0.19
ClinPred		0.018	T
GERP RS		1.1
Varity_R		0.049
gMVP		0.58

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: rs148576400; hg19: chr16-19519044;