chrX-133754180-TAAAA-T

Variant names:

• chrX-133754180-TAAAA-T
• rs370737647
• NM_004484.4:c.338-8_338-5delTTTT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

The NM_004484.4(GPC3):​c.338-8_338-5delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 941,468 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.00032 (0 hom. 0 hem.)
• Consequence: GPC3 NM_004484.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.240

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000323 (279/864964) while in subpopulation AFR AF= 0.000391 (8/20468). AF 95% confidence interval is 0.00033. There are 0 homozygotes in gnomad4_exome. There are 0 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.338-8_338-5delTTTT		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.338-8_338-5delTTTT		splice_region_variant, intron_variant	Intron 2 of 7	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 1 AN: 76504 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 17848

Gnomad AFR AF: 0.0000485

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000323 AC: 279 AN: 864964 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 253134

Gnomad4 AFR exome AF: 0.000391

Gnomad4 AMR exome AF: 0.000187

Gnomad4 ASJ exome AF: 0.000177

Gnomad4 EAS exome AF: 0.0000347

Gnomad4 SAS exome AF: 0.000136

Gnomad4 FIN exome AF: 0.0000908

Gnomad4 NFE exome AF: 0.000369

Gnomad4 OTH exome AF: 0.000317

GnomAD4 genome AF: 0.0000131 AC: 1 AN: 76504 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 17848

Gnomad4 AFR AF: 0.0000485

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000742 Hom.: 71

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs370737647; hg19: chrX-132888207;