Genetic Variant GDPD2:p.Glu3Lys (chrX-70424991-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_017711.4(GDPD2):c.7G>A(p.Glu3Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,186,936 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E3D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.00011 ( 0 hom. 26 hem. )

Consequence

GDPD2
NM_017711.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.284

Variant links:

Genes affected

GDPD2 (HGNC:25974): (glycerophosphodiester phosphodiesterase domain containing 2) This gene encodes a member of the glycerophosphodiester phosphodiesterase enzyme family. The encoded protein hydrolyzes glycerophosphoinositol to produce inositol 1-phosphate and glycerol. This protein may have a role in osteoblast differentiation and growth. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2010]

GDPD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.048963875).

BS2

High Hemizygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDPD2	NM_017711.4 link	c.7G>A	p.Glu3Lys	missense_variant	Exon 2 of 16	ENST00000374382.4	NP_060181.2	Q9HCC8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GDPD2	ENST00000374382.4 link	c.7G>A	p.Glu3Lys	missense_variant	Exon 2 of 16	1	NM_017711.4	ENSP00000363503.3	Q9HCC8-1
GDPD2	ENST00000453994.6 link	c.7G>A	p.Glu3Lys	missense_variant	Exon 2 of 17	2		ENSP00000414019.2	Q9HCC8-3
GDPD2	ENST00000536730.5 link	c.-132-363G>A		intron_variant	Intron 1 of 14	2		ENSP00000445982.1	Q9HCC8-2
GDPD2	ENST00000538649.5 link	c.-28-772G>A		intron_variant	Intron 1 of 13	2		ENSP00000444601.1	Q9HCC8-2

Frequencies

GnomAD3 genomes

AF:

0.0000981

AC:

AN:

112111

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

34289

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000207

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000341

AC:

AN:

146559

Hom.:

AF XY:

0.00

AC XY:

AN XY:

43563

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000806

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000105

AC:

113

AN:

1074825

Hom.:

Cov.:

AF XY:

0.0000749

AC XY:

AN XY:

346913

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000309

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000391

Gnomad4 FIN exome

AF:

0.0000256

Gnomad4 NFE exome

AF:

0.000123

Gnomad4 OTH exome

AF:

0.000155

GnomAD4 genome

AF:

0.0000981

AC:

AN:

112111

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

34289

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000207

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000668

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7G>A (p.E3K) alteration is located in exon 2 (coding exon 1) of the GDPD2 gene. This alteration results from a G to A substitution at nucleotide position 7, causing the glutamic acid (E) at amino acid position 3 to be replaced by a lysine (K). 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

0.087

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

.;T

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.75

N;N

REVEL

Benign

0.021

Sift

Benign

0.074

T;T

Sift4G

Uncertain

0.039

D;D

Polyphen

0.0040

.;B

Vest4

0.22

MVP

0.18

MPC

0.47

ClinPred

0.043

GERP RS

2.3

Varity_R

0.10

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over