rs755510528

Variant names:

• chrX-133953138-T-C
• rs755510528
• NM_004484.4:c.249A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-133953138-T-C
• chrX-133953138-T-G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004484.4(GPC3):​c.249A>G​(p.Leu83Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000915 in 1,092,838 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L83L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000092 (0 hom. 4 hem.)
• Consequence: GPC3 NM_004484.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.820
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant X-133953138-T-C is Benign according to our data. Variant chrX-133953138-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 476653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.82 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 4 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.249A>G	p.Leu83Leu	synonymous	Exon 2 of 8	NP_004475.1
	GPC3	NM_001164617.2		c.249A>G	p.Leu83Leu	synonymous	Exon 2 of 9	NP_001158089.1
	GPC3	NM_001164618.2		c.249A>G	p.Leu83Leu	synonymous	Exon 2 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.249A>G	p.Leu83Leu	synonymous	Exon 2 of 8	ENSP00000359854.3
	GPC3	ENST00000394299.7	TSL:1	c.249A>G	p.Leu83Leu	synonymous	Exon 2 of 9	ENSP00000377836.2
	GPC3	ENST00000631057.2	TSL:1	c.175+32137A>G		intron	N/A	ENSP00000486325.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000915 AC: 10 AN: 1092838 Hom.: 0 Cov.: 29 AF XY: 0.0000112 AC XY: 4 AN XY: 358308

African (AFR) AF: 0.00 AC: 0 AN: 26298

American (AMR) AF: 0.00 AC: 0 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19357

East Asian (EAS) AF: 0.00 AC: 0 AN: 30191

South Asian (SAS) AF: 0.00 AC: 0 AN: 54009

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 837191

Other (OTH) AF: 0.00 AC: 0 AN: 45942

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.8
DANN	Benign	0.80
PhyloP100		-0.82

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: rs755510528; hg19: chrX-133087165;