rs200265913

Positions:

• chrX-133596587-T-A
• chrX-133596587-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_004484.4(GPC3):​c.1426A>T​(p.Met476Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,097,560 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M476V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000014 (0 hom. 5 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:1
• Conservation: PhyloP100: 4.60

Genes affected

GPC3 (HGNC:4451): (glypican 3) Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The protein encoded by this gene can bind to and inhibit the dipeptidyl peptidase activity of CD26, and it can induce apoptosis in certain cell types. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome, also known as Simpson dysmorphia syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31279165).
• BP6: Variant X-133596587-T-A is Benign according to our data. Variant chrX-133596587-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134502.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_benign=1}. Variant chrX-133596587-T-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPC3	NM_004484.4	c.1426A>T	p.Met476Leu	missense_variant	7/8	ENST00000370818.8
GPC3	NM_001164617.2	c.1495A>T	p.Met499Leu	missense_variant	8/9
GPC3	NM_001164618.2	c.1378A>T	p.Met460Leu	missense_variant	7/8
GPC3	NM_001164619.2	c.1264A>T	p.Met422Leu	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPC3	ENST00000370818.8	c.1426A>T	p.Met476Leu	missense_variant	7/8	1	NM_004484.4	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000137 AC: 15 AN: 1097560 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 5 AN XY: 362928

Gnomad4 AFR exome AF: 0.000455

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: 0.00

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 14, 2019

- -

Wilms tumor 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.28	T;.;.
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.66	N;.;.
MutationTaster	Benign	0.65	N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.58	N;N;.
REVEL	Benign	0.21
Sift	Benign	0.66	T;T;.
Sift4G	Benign	0.49	T;T;T
Polyphen		0.029	B;.;.
Vest4		0.48
MutPred		0.35		Loss of ubiquitination at K480 (P = 0.0429);.;.;
MVP		0.91
MPC		0.17
ClinPred		0.57	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.39

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: rs200265913; hg19: chrX-132730615;