rs751413609

Variant names:

• chrX-133536296-GTCAA-G
• rs751413609
• NM_004484.4:c.1574-7_1574-4delTTGA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004484.4(GPC3):​c.1574-7_1574-4delTTGA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000674 in 1,190,583 control chromosomes in the GnomAD database, including 1 homozygotes. There are 257 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., 18 hem., cov: 20)
  • Exomes 𝑓: 0.00069 (1 hom. 239 hem.)
• Consequence: GPC3 NM_004484.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.42
• 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 -16 ACMG points.

• BP6: Variant X-133536296-GTCAA-G is Benign according to our data. Variant chrX-133536296-GTCAA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000485 (54/111273) while in subpopulation NFE AF = 0.000905 (48/53053). AF 95% confidence interval is 0.000701. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 18 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.1574-7_1574-4delTTGA		splice_region intron	N/A	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.1643-7_1643-4delTTGA		splice_region intron	N/A	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.1526-7_1526-4delTTGA		splice_region intron	N/A	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.1574-7_1574-4delTTGA		splice_region intron	N/A	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.1643-7_1643-4delTTGA		splice_region intron	N/A	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.1412-7_1412-4delTTGA		splice_region intron	N/A	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 54 AN: 111219 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000981

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000282

Gnomad SAS AF: 0.000385

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000905

Gnomad OTH AF: 0.000670

GnomAD2 exomes AF: 0.000666 AC: 121 AN: 181817 AF XY: 0.000865

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000626

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000693 AC: 748 AN: 1079310 Hom.: 1 AF XY: 0.000690 AC XY: 239 AN XY: 346236

African (AFR) AF: 0.000192 AC: 5 AN: 26060

American (AMR) AF: 0.0000853 AC: 3 AN: 35189

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19276

East Asian (EAS) AF: 0.00 AC: 0 AN: 30142

South Asian (SAS) AF: 0.000372 AC: 20 AN: 53719

European-Finnish (FIN) AF: 0.0000987 AC: 4 AN: 40514

Middle Eastern (MID) AF: 0.00245 AC: 10 AN: 4085

European-Non Finnish (NFE) AF: 0.000826 AC: 681 AN: 824860

Other (OTH) AF: 0.000550 AC: 25 AN: 45465

GnomAD4 genome AF: 0.000485 AC: 54 AN: 111273 Hom.: 0 Cov.: 20 AF XY: 0.000538 AC XY: 18 AN XY: 33459

African (AFR) AF: 0.0000979 AC: 3 AN: 30640

American (AMR) AF: 0.00 AC: 0 AN: 10398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.000283 AC: 1 AN: 3531

South Asian (SAS) AF: 0.000386 AC: 1 AN: 2591

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6007

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000905 AC: 48 AN: 53053

Other (OTH) AF: 0.000661 AC: 1 AN: 1512

Alfa AF: 0.000545 Hom.: 5

Bravo AF: 0.000563

EpiCase AF: 0.00191

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=92/8	polymorphism (auto)

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: rs751413609; hg19: chrX-132670324;