rs148951753

Variant names:

• chrX-133753625-T-C
• rs148951753
• NM_004484.4:c.889A>G
• GPC3 p.Arg297Gly

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_004484.4(GPC3):​c.889A>G​(p.Arg297Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,209,352 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 95 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R297K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00027 (0 hom. 90 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.941
• 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: ClinGen, Orphanet
• Simpson-Golabi-Behmel syndrome type 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28073817).
• BP6: Variant X-133753625-T-C is Benign according to our data. Variant chrX-133753625-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 415278.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 = 0.000187 (21/112276) while in subpopulation NFE AF = 0.000357 (19/53245). AF 95% confidence interval is 0.000233. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 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.889A>G	p.Arg297Gly	missense	Exon 3 of 8	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.889A>G	p.Arg297Gly	missense	Exon 3 of 9	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.841A>G	p.Arg281Gly	missense	Exon 3 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.889A>G	p.Arg297Gly	missense	Exon 3 of 8	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.889A>G	p.Arg297Gly	missense	Exon 3 of 9	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.727A>G	p.Arg243Gly	missense	Exon 2 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes AF: 0.000187 AC: 21 AN: 112223 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000648

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: 0.000357

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000207 AC: 38 AN: 183321 AF XY: 0.000133

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000452

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000274 AC: 301 AN: 1097076 Hom.: 0 Cov.: 32 AF XY: 0.000248 AC XY: 90 AN XY: 362454

African (AFR) AF: 0.00 AC: 0 AN: 26380

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54116

European-Finnish (FIN) AF: 0.0000987 AC: 4 AN: 40527

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

European-Non Finnish (NFE) AF: 0.000342 AC: 288 AN: 841074

Other (OTH) AF: 0.000195 AC: 9 AN: 46059

GnomAD4 genome AF: 0.000187 AC: 21 AN: 112276 Hom.: 0 Cov.: 23 AF XY: 0.000145 AC XY: 5 AN XY: 34440

African (AFR) AF: 0.0000647 AC: 2 AN: 30931

American (AMR) AF: 0.00 AC: 0 AN: 10597

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3569

South Asian (SAS) AF: 0.00 AC: 0 AN: 2655

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6189

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000357 AC: 19 AN: 53245

Other (OTH) AF: 0.00 AC: 0 AN: 1537

Alfa AF: 0.000192 Hom.: 8

Bravo AF: 0.000159

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.94
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.25
Sift	Benign	0.099	T
Sift4G	Uncertain	0.019	D
PromoterAI		-0.0072	Neutral
Varity_R		0.63
gMVP		0.63
Mutation Taster		=94/6	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs148951753;

hg19: chrX-132887652;