13-91693403-C-T

Variant names:

• chr13-91693403-C-T
• rs2035802337
• NM_004466.6:c.542C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004466.6(GPC5):​c.542C>T​(p.Pro181Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPC5 NM_004466.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

Genes affected

GPC5 (HGNC:4453): (glypican 5) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC5	NM_004466.6	c.542C>T	p.Pro181Leu	missense_variant	Exon 3 of 8	ENST00000377067.9	NP_004457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC5	ENST00000377067.9	c.542C>T	p.Pro181Leu	missense_variant	Exon 3 of 8	1	NM_004466.6	ENSP00000366267.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.542C>T (p.P181L) alteration is located in exon 3 (coding exon 3) of the GPC5 gene. This alteration results from a C to T substitution at nucleotide position 542, causing the proline (P) at amino acid position 181 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-8.3	D;.
REVEL	Uncertain	0.35
Sift	Benign	0.031	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.68	P;.
Vest4		0.61
MutPred		0.61		Gain of catalytic residue at V183 (P = 0.001);.;
MVP		0.27
MPC		0.22
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.60
gMVP		0.65

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: rs2035802337; hg19: chr13-92345657;