NM_004484.4:c.1426A>T

Variant names:

• chrX-133596587-T-A
• rs200265913
• NM_004484.4:c.1426A>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_004484.4(GPC3):​c.1426A>T​(p.Met476Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,097,560 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M476V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000014 (0 hom. 5 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1 O:1
• Conservation: PhyloP100: 4.60
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31279165).
• BP6: Variant X-133596587-T-A is Benign according to our data. Variant chrX-133596587-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134502.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000137 (15/1097560) while in subpopulation AFR AF = 0.000455 (12/26387). AF 95% confidence interval is 0.000262. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 5 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.1426A>T	p.Met476Leu	missense	Exon 7 of 8	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.1495A>T	p.Met499Leu	missense	Exon 8 of 9	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.1378A>T	p.Met460Leu	missense	Exon 7 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.1426A>T	p.Met476Leu	missense	Exon 7 of 8	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.1495A>T	p.Met499Leu	missense	Exon 8 of 9	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.1264A>T	p.Met422Leu	missense	Exon 6 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.0000137 AC: 15 AN: 1097560 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 5 AN XY: 362928

African (AFR) AF: 0.000455 AC: 12 AN: 26387

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841517

Other (OTH) AF: 0.0000651 AC: 3 AN: 46075

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	Simpson-Golabi-Behmel syndrome type 1;CN033288:Wilms tumor 1 (1)
-	-	1	Wilms tumor 1 (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.66	N
PhyloP100		4.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.21
Sift	Benign	0.66	T
Sift4G	Benign	0.49	T
Polyphen		0.029	B
Vest4		0.48
MutPred		0.35		Loss of ubiquitination at K480 (P = 0.0429)
MVP		0.91
MPC		0.17
ClinPred		0.57	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.39
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200265913; hg19: chrX-132730615;