X-133336655-A-G

Variant names:

• chrX-133336655-A-G
• rs41537046
• NM_001448.3:c.319+2528T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001448.3(GPC4):​c.319+2528T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 109,947 control chromosomes in the GnomAD database, including 6,447 homozygotes. There are 11,388 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (6447 hom., 11388 hem., cov: 21)
• Consequence: GPC4 NM_001448.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.336
• Publications: 1 publications found

Genes affected

GPC4 (HGNC:4452): (glypican 4) 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 GPC4 gene is adjacent to the 3' end of GPC3 and may also play a role in Simpson-Golabi-Behmel syndrome. [provided by RefSeq, Jul 2008]

GPC4 Gene-Disease associations (from GenCC):

• Keipert syndrome

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001448.3. 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
	GPC4	NM_001448.3	MANE Select	c.319+2528T>C		intron	N/A	NP_001439.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC4	ENST00000370828.4	TSL:1 MANE Select	c.319+2528T>C		intron	N/A	ENSP00000359864.3	O75487-1
	GPC4	ENST00000887818.1		c.319+2528T>C		intron	N/A	ENSP00000557877.1
	GPC4	ENST00000931828.1		c.319+2528T>C		intron	N/A	ENSP00000601887.1

Frequencies

GnomAD3 genomes AF: 0.371 AC: 40746 AN: 109894 Hom.: 6443 Cov.: 21

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.308

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.351

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.371 AC: 40770 AN: 109947 Hom.: 6447 Cov.: 21 AF XY: 0.353 AC XY: 11388 AN XY: 32253

African (AFR) AF: 0.597 AC: 17929 AN: 30043

American (AMR) AF: 0.234 AC: 2432 AN: 10394

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 838 AN: 2627

East Asian (EAS) AF: 0.432 AC: 1487 AN: 3441

South Asian (SAS) AF: 0.493 AC: 1239 AN: 2512

European-Finnish (FIN) AF: 0.219 AC: 1274 AN: 5813

Middle Eastern (MID) AF: 0.304 AC: 65 AN: 214

European-Non Finnish (NFE) AF: 0.279 AC: 14711 AN: 52731

Other (OTH) AF: 0.350 AC: 524 AN: 1497

Alfa AF: 0.310 Hom.: 3481

Bravo AF: 0.381

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.75
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

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: rs41537046;

hg19: chrX-132470683;