rs755823884

Variant names:

• chrX-133536266-T-C
• rs755823884
• NM_004484.4:c.1601A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_004484.4(GPC3):​c.1601A>G​(p.Asp534Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000549 in 1,092,363 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D534N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.18
• Publications: 1 publications found

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]

GPC3 Gene-Disease associations (from GenCC):

• Simpson-Golabi-Behmel syndrome

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Simpson-Golabi-Behmel syndrome type 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13874897).
• BP6: Variant X-133536266-T-C is Benign according to our data. Variant chrX-133536266-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 543095.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000549 (6/1092363) while in subpopulation AMR AF = 0.00017 (6/35200). AF 95% confidence interval is 0.000074. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004484.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	NM_004484.4	MANE Select	c.1601A>G	p.Asp534Gly	missense	Exon 8 of 8	NP_004475.1
	GPC3	NM_001164617.2		c.1670A>G	p.Asp557Gly	missense	Exon 9 of 9	NP_001158089.1
	GPC3	NM_001164618.2		c.1553A>G	p.Asp518Gly	missense	Exon 8 of 8	NP_001158090.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	ENST00000370818.8	TSL:1 MANE Select	c.1601A>G	p.Asp534Gly	missense	Exon 8 of 8	ENSP00000359854.3
	GPC3	ENST00000394299.7	TSL:1	c.1670A>G	p.Asp557Gly	missense	Exon 9 of 9	ENSP00000377836.2
	GPC3	ENST00000631057.2	TSL:1	c.1439A>G	p.Asp480Gly	missense	Exon 7 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.0000383 AC: 7 AN: 182567 AF XY: 0.0000446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000255

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 6 AN: 1092363 Hom.: 0 Cov.: 30 AF XY: 0.00000559 AC XY: 2 AN XY: 357871

African (AFR) AF: 0.00 AC: 0 AN: 26284

American (AMR) AF: 0.000170 AC: 6 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19352

East Asian (EAS) AF: 0.00 AC: 0 AN: 30178

South Asian (SAS) AF: 0.00 AC: 0 AN: 54015

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836772

Other (OTH) AF: 0.00 AC: 0 AN: 45908

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.053	T
Sift4G	Uncertain	0.027	D
Polyphen		0.92	P
Vest4		0.15
MutPred		0.55		Gain of catalytic residue at D534 (P = 0.1187)
MVP		0.50
MPC		0.35
ClinPred		0.19	T
GERP RS		4.8
Varity_R		0.28
gMVP		0.59
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs755823884; hg19: chrX-132670294;