rs1048369

chrX-133303309-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001448.3(GPC4):c.1325C>T(p.Ala442Val) variant causes a missense change. The variant allele was found at a frequency of 0.312 in 1,206,963 control chromosomes in the GnomAD database, including 42,163 homozygotes. There are 125,172 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.38 (6635 hom., 11938 hem., cov: 22)
  • Exomes 𝑓: 0.31 (35528 hom. 113234 hem.)
• Consequence: GPC4 NM_001448.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.92

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4469028E-4).
• BP6: Variant X-133303309-G-A is Benign according to our data. Variant chrX-133303309-G-A is described in ClinVar as [Benign]. Clinvar id is 1285303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPC4	NM_001448.3	c.1325C>T	p.Ala442Val	missense_variant	8/9	ENST00000370828.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPC4	ENST00000370828.4	c.1325C>T	p.Ala442Val	missense_variant	8/9	1	NM_001448.3	P1

Frequencies

GnomAD3 genomes AF: 0.382 AC: 42064 AN: 110248 Hom.: 6633 Cov.: 22 AF XY: 0.366 AC XY: 11909 AN XY: 32520

Gnomad AFR AF: 0.594

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.369

GnomAD3 exomes AF: 0.330 AC: 59799 AN: 181319 Hom.: 7078 AF XY: 0.339 AC XY: 22333 AN XY: 65925

Gnomad AFR exome AF: 0.599

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.369

Gnomad EAS exome AF: 0.444

Gnomad SAS exome AF: 0.503

Gnomad FIN exome AF: 0.246

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.307

GnomAD4 exome AF: 0.305 AC: 334730 AN: 1096658 Hom.: 35528 Cov.: 31 AF XY: 0.312 AC XY: 113234 AN XY: 362400

Gnomad4 AFR exome AF: 0.607

Gnomad4 AMR exome AF: 0.187

Gnomad4 ASJ exome AF: 0.363

Gnomad4 EAS exome AF: 0.399

Gnomad4 SAS exome AF: 0.498

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.284

Gnomad4 OTH exome AF: 0.339

GnomAD4 genome AF: 0.382 AC: 42091 AN: 110305 Hom.: 6635 Cov.: 22 AF XY: 0.366 AC XY: 11938 AN XY: 32587

Gnomad4 AFR AF: 0.594

Gnomad4 AMR AF: 0.255

Gnomad4 ASJ AF: 0.369

Gnomad4 EAS AF: 0.443

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.293

Gnomad4 OTH AF: 0.367

Alfa AF: 0.316 Hom.: 29736

Bravo AF: 0.389

TwinsUK AF: 0.276 AC: 1023

ALSPAC AF: 0.288 AC: 831

ESP6500AA AF: 0.597 AC: 2290

ESP6500EA AF: 0.295 AC: 1986

ExAC AF: 0.349 AC: 42354

EpiCase AF: 0.301

EpiControl AF: 0.299

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Keipert syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.00014	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.0000011	P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.21
Sift	Benign	0.099	T
Sift4G	Benign	0.067	T
Polyphen		0.90	P
Vest4		0.063
MPC		1.5
ClinPred		0.030	T
GERP RS		4.7
Varity_R		0.15
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs1048369; hg19: chrX-132437337; COSMIC: COSV63697202;