rs1060502171

Variant names:

• chrX-133754159-C-A
• rs1060502171
• NM_004484.4:c.355G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-133754159-C-A
• chrX-133754159-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_004484.4(GPC3):​c.355G>T​(p.Val119Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.00024 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.17
• Publications: 5 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	NM_004484.4	MANE Select	c.355G>T	p.Val119Phe	missense	Exon 3 of 8	NP_004475.1
	GPC3	NM_001164617.2		c.355G>T	p.Val119Phe	missense	Exon 3 of 9	NP_001158089.1
	GPC3	NM_001164618.2		c.307G>T	p.Val103Phe	missense	Exon 3 of 8	NP_001158090.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	ENST00000370818.8	TSL:1 MANE Select	c.355G>T	p.Val119Phe	missense	Exon 3 of 8	ENSP00000359854.3
	GPC3	ENST00000394299.7	TSL:1	c.355G>T	p.Val119Phe	missense	Exon 3 of 9	ENSP00000377836.2
	GPC3	ENST00000631057.2	TSL:1	c.193G>T	p.Val65Phe	missense	Exon 2 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes AF: 0.0000223 AC: 2 AN: 89522 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000837

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

GnomAD2 exomes AF: 0.000183 AC: 28 AN: 153262 AF XY: 0.00

Gnomad AFR exome AF: 0.000356

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.000155

Gnomad EAS exome AF: 0.000292

Gnomad FIN exome AF: 0.0000677

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000237 AC: 221 AN: 930592 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 271614

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

African (AFR) AF: 0.000452 AC: 10 AN: 22105

American (AMR) AF: 0.000761 AC: 23 AN: 30213

Ashkenazi Jewish (ASJ) AF: 0.000407 AC: 7 AN: 17213

East Asian (EAS) AF: 0.000583 AC: 16 AN: 27428

South Asian (SAS) AF: 0.000585 AC: 24 AN: 41054

European-Finnish (FIN) AF: 0.0000798 AC: 3 AN: 37584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3472

European-Non Finnish (NFE) AF: 0.000177 AC: 126 AN: 711732

Other (OTH) AF: 0.000302 AC: 12 AN: 39791

⚠️ 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: 0.0000223 AC: 2 AN: 89555 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 21569

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

African (AFR) AF: 0.0000835 AC: 2 AN: 23957

American (AMR) AF: 0.00 AC: 0 AN: 7719

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2225

East Asian (EAS) AF: 0.00 AC: 0 AN: 2947

South Asian (SAS) AF: 0.00 AC: 0 AN: 1833

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 180

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 45316

Other (OTH) AF: 0.00 AC: 0 AN: 1173

⚠️ 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.

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Simpson-Golabi-Behmel syndrome type 1;CN033288:Wilms tumor 1 (1)
-	1	-	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.80
MutPred		0.76		Loss of ubiquitination at K123 (P = 0.1498)
MVP		0.83
MPC		0.28
ClinPred		0.072	T
GERP RS		5.3
PromoterAI		-0.0038	Neutral
Varity_R		0.69
gMVP		0.94
Mutation Taster		=69/31	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: rs1060502171; hg19: chrX-132888186;