Genetic Variant GPC4:c.1469-4C>G (chrX-133303073-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001448.3(GPC4):c.1469-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,466 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

GPC4
NM_001448.3 splice_region, intron

Scores

Splicing: ADA: 0.6116

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00600

Publications

0 publications found

Variant links:

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

GPC4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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.1469-4C>G		splice_region intron	N/A	NP_001439.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GPC4	ENST00000370828.4	TSL:1 MANE Select	c.1469-4C>G	splice_region intron	N/A	ENSP00000359864.3	O75487-1
GPC4	ENST00000887818.1		c.1469-4C>G	splice_region intron	N/A	ENSP00000557877.1
GPC4	ENST00000931828.1		c.1469-4C>G	splice_region intron	N/A	ENSP00000601887.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000552

AC:

AN:

181288

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1095466

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361292

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26254

American (AMR)

AF:

0.00

AC:

AN:

34814

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19282

East Asian (EAS)

AF:

0.00

AC:

AN:

30189

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840577

Other (OTH)

AF:

0.00

AC:

AN:

45963

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

(source)

DANN

Benign

0.52

PhyloP100

0.0060

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.61

dbscSNV1_RF

Benign

0.55

SpliceAI score (max)

0.90

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.90

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over