X-133753638-A-G

Variant names:

• chrX-133753638-A-G
• rs61754633
• NM_004484.4:c.876T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004484.4(GPC3):​c.876T>C​(p.Ile292Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000285 in 1,210,009 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 126 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.00029 (0 hom. 119 hem.)
• Consequence: GPC3 NM_004484.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.364
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.027).
• BP6: Variant X-133753638-A-G is Benign according to our data. Variant chrX-133753638-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.364 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00024 (27/112343) while in subpopulation NFE AF = 0.000432 (23/53261). AF 95% confidence interval is 0.000294. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	NM_004484.4	MANE Select	c.876T>C	p.Ile292Ile	synonymous	Exon 3 of 8	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.876T>C	p.Ile292Ile	synonymous	Exon 3 of 9	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.828T>C	p.Ile276Ile	synonymous	Exon 3 of 8	NP_001158090.1	B4DTD8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	ENST00000370818.8	TSL:1 MANE Select	c.876T>C	p.Ile292Ile	synonymous	Exon 3 of 8	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.876T>C	p.Ile292Ile	synonymous	Exon 3 of 9	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.714T>C	p.Ile238Ile	synonymous	Exon 2 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes AF: 0.000240 AC: 27 AN: 112289 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000432

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000229 AC: 42 AN: 183334 AF XY: 0.000324

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000477

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000290 AC: 318 AN: 1097666 Hom.: 0 Cov.: 32 AF XY: 0.000328 AC XY: 119 AN XY: 363036

African (AFR) AF: 0.000152 AC: 4 AN: 26393

American (AMR) AF: 0.0000568 AC: 2 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00266 AC: 11 AN: 4136

European-Non Finnish (NFE) AF: 0.000343 AC: 289 AN: 841610

Other (OTH) AF: 0.000260 AC: 12 AN: 46073

GnomAD4 genome AF: 0.000240 AC: 27 AN: 112343 Hom.: 0 Cov.: 23 AF XY: 0.000203 AC XY: 7 AN XY: 34495

African (AFR) AF: 0.0000970 AC: 3 AN: 30937

American (AMR) AF: 0.00 AC: 0 AN: 10607

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.000376 AC: 1 AN: 2660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000432 AC: 23 AN: 53261

Other (OTH) AF: 0.00 AC: 0 AN: 1540

Alfa AF: 0.000255 Hom.: 2

Bravo AF: 0.000257

EpiCase AF: 0.000327

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Simpson-Golabi-Behmel syndrome type 1 (1)
-	-	1	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.4
DANN	Benign	0.70
PhyloP100		-0.36
PromoterAI		0.030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs61754633; hg19: chrX-132887665;