NM_004484.4:c.1631C>T

Variant names:

• chrX-133536236-G-A
• rs375606908
• NM_004484.4:c.1631C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004484.4(GPC3):​c.1631C>T​(p.Pro544Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,199,749 control chromosomes in the GnomAD database, including 1 homozygotes. There are 62 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 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. P544R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (1 hom., 4 hem., cov: 21)
  • Exomes 𝑓: 0.00016 (0 hom. 58 hem.)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.464
• Publications: 2 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008171827).
• BP6: Variant X-133536236-G-A is Benign according to our data. Variant chrX-133536236-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000128 (14/109594) while in subpopulation EAS AF = 0.00404 (14/3467). AF 95% confidence interval is 0.00244. There are 1 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 4 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.1631C>T	p.Pro544Leu	missense	Exon 8 of 8	NP_004475.1	I6QTG3
	GPC3	NM_001164617.2		c.1700C>T	p.Pro567Leu	missense	Exon 9 of 9	NP_001158089.1	P51654-3
	GPC3	NM_001164618.2		c.1583C>T	p.Pro528Leu	missense	Exon 8 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.1631C>T	p.Pro544Leu	missense	Exon 8 of 8	ENSP00000359854.3	P51654-1
	GPC3	ENST00000394299.7	TSL:1	c.1700C>T	p.Pro567Leu	missense	Exon 9 of 9	ENSP00000377836.2	P51654-3
	GPC3	ENST00000631057.2	TSL:1	c.1469C>T	p.Pro490Leu	missense	Exon 7 of 7	ENSP00000486325.1	P51654-2

Frequencies

GnomAD3 genomes AF: 0.000128 AC: 14 AN: 109536 Hom.: 1 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00403

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: 0.000317 AC: 58 AN: 182945 AF XY: 0.000326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00404

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000157 AC: 171 AN: 1090155 Hom.: 0 Cov.: 30 AF XY: 0.000163 AC XY: 58 AN XY: 355779

African (AFR) AF: 0.00 AC: 0 AN: 26219

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19339

East Asian (EAS) AF: 0.00457 AC: 138 AN: 30178

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53963

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.0000252 AC: 21 AN: 834807

Other (OTH) AF: 0.000240 AC: 11 AN: 45812

GnomAD4 genome AF: 0.000128 AC: 14 AN: 109594 Hom.: 1 Cov.: 21 AF XY: 0.000126 AC XY: 4 AN XY: 31866

African (AFR) AF: 0.00 AC: 0 AN: 30073

American (AMR) AF: 0.00 AC: 0 AN: 10164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2628

East Asian (EAS) AF: 0.00404 AC: 14 AN: 3467

South Asian (SAS) AF: 0.00 AC: 0 AN: 2469

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 211

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52718

Other (OTH) AF: 0.00 AC: 0 AN: 1480

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000204

ExAC AF: 0.000305 AC: 37

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)
-	-	1	Simpson-Golabi-Behmel syndrome type 1 (1)
-	-	1	Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.75
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.46
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.033
Sift	Benign	0.16	T
Sift4G	Benign	0.15	T
Polyphen		0.050	B
Vest4		0.15
MutPred		0.57		Loss of loop (P = 0.0128)
MVP		0.24
MPC		0.18
ClinPred		0.020	T
GERP RS		-0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.26
Mutation Taster		=99/1	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: rs375606908; hg19: chrX-132670264;