rs1490568896

Variant names:

• chrX-133754180-T-A
• rs1490568896
• NM_004484.4:c.338-4A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_004484.4(GPC3):​c.338-4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., 0 hem., cov: 18)
  • Exomes 𝑓: 0.000075 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GPC3 NM_004484.4 splice_region, intron
• Scores: Splicing: ADA: 0.00007847
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.447
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant X-133754180-T-A is Benign according to our data. Variant chrX-133754180-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 476654.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.338-4A>T		splice_region_variant, intron_variant	Intron 2 of 7	ENST00000370818.8	NP_004475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8	c.338-4A>T		splice_region_variant, intron_variant	Intron 2 of 7	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes AF: 0.000249 AC: 19 AN: 76423 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000704

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000290

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000749 AC: 65 AN: 867494 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 254276

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000439 AC: 9 AN: 20501

American (AMR) AF: 0.0000746 AC: 2 AN: 26800

Ashkenazi Jewish (ASJ) AF: 0.000176 AC: 3 AN: 17020

East Asian (EAS) AF: 0.000139 AC: 4 AN: 28838

South Asian (SAS) AF: 0.0000225 AC: 1 AN: 44357

European-Finnish (FIN) AF: 0.000483 AC: 16 AN: 33116

Middle Eastern (MID) AF: 0.000326 AC: 1 AN: 3070

European-Non Finnish (NFE) AF: 0.0000366 AC: 24 AN: 655839

Other (OTH) AF: 0.000132 AC: 5 AN: 37953

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000249 AC: 19 AN: 76414 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 17816

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000291 AC: 6 AN: 20625

American (AMR) AF: 0.00 AC: 0 AN: 7247

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1944

East Asian (EAS) AF: 0.00 AC: 0 AN: 2596

South Asian (SAS) AF: 0.00 AC: 0 AN: 1679

European-Finnish (FIN) AF: 0.000704 AC: 2 AN: 2840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 124

European-Non Finnish (NFE) AF: 0.000290 AC: 11 AN: 37897

Other (OTH) AF: 0.00 AC: 0 AN: 1001

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Wilms tumor 1 Benign:1

Jul 21, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.6
DANN	Benign	0.51
PhyloP100		-0.45
PromoterAI		0.0072	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000078
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.060		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: rs1490568896; hg19: chrX-132888207; COSMIC: COSV104685920; COSMIC: COSV104685920;