NM_001448.3:c.1469-8dupT

Variant names:

• chrX-133303076-T-TA
• rs747604482
• NM_001448.3:c.1469-8dupT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001448.3(GPC4):​c.1469-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000469 in 1,194,860 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000047 (0 hom. 9 hem.)
• Consequence: GPC4 NM_001448.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.01
• Publications: 0 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: XLR, XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP6: Variant X-133303076-T-TA is Benign according to our data. Variant chrX-133303076-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 710909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 9 XL,XLR gene

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.1469-8dupT		splice_region 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.1469-8_1469-7insT		splice_region intron	N/A	ENSP00000359864.3	O75487-1
	GPC4	ENST00000887818.1		c.1469-8_1469-7insT		splice_region intron	N/A	ENSP00000557877.1
	GPC4	ENST00000931828.1		c.1469-8_1469-7insT		splice_region intron	N/A	ENSP00000601887.1

Frequencies

GnomAD3 genomes AF: 0.0000453 AC: 5 AN: 110464 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000329

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: 0.0000760

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 4 AN: 166052 AF XY: 0.0000173

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000415

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000133

Gnomad OTH exome AF: 0.000249

GnomAD4 exome AF: 0.0000470 AC: 51 AN: 1084396 Hom.: 0 Cov.: 29 AF XY: 0.0000254 AC XY: 9 AN XY: 354548

African (AFR) AF: 0.00 AC: 0 AN: 25995

American (AMR) AF: 0.0000291 AC: 1 AN: 34402

Ashkenazi Jewish (ASJ) AF: 0.0000525 AC: 1 AN: 19053

East Asian (EAS) AF: 0.000100 AC: 3 AN: 29967

South Asian (SAS) AF: 0.0000564 AC: 3 AN: 53153

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40271

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4081

European-Non Finnish (NFE) AF: 0.0000481 AC: 40 AN: 831932

Other (OTH) AF: 0.0000439 AC: 2 AN: 45542

GnomAD4 genome AF: 0.0000453 AC: 5 AN: 110464 Hom.: 0 Cov.: 23 AF XY: 0.0000303 AC XY: 1 AN XY: 32992

African (AFR) AF: 0.0000329 AC: 1 AN: 30397

American (AMR) AF: 0.00 AC: 0 AN: 10396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2624

East Asian (EAS) AF: 0.00 AC: 0 AN: 3529

South Asian (SAS) AF: 0.00 AC: 0 AN: 2611

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5859

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000760 AC: 4 AN: 52662

Other (OTH) AF: 0.00 AC: 0 AN: 1469

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.0
Mutation Taster		=100/0	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: rs747604482; hg19: chrX-132437104;