4-83306215-G-C

Variant names:

• chr4-83306215-G-C
• NM_001098540.3:c.1194C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001098540.3(HPSE):​c.1194C>G​(p.Phe398Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HPSE NM_001098540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.141

Genes affected

HPSE (HGNC:5164): (heparanase) Heparan sulfate proteoglycans are major components of the basement membrane and extracellular matrix. The protein encoded by this gene is an enzyme that cleaves heparan sulfate proteoglycans to permit cell movement through remodeling of the extracellular matrix. In addition, this cleavage can release bioactive molecules from the extracellular matrix. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37871212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPSE	NM_001098540.3	c.1194C>G	p.Phe398Leu	missense_variant	Exon 9 of 12	ENST00000311412.10	NP_001092010.1
HPSE	NM_006665.6	c.1194C>G	p.Phe398Leu	missense_variant	Exon 10 of 13		NP_006656.2
HPSE	NM_001199830.1	c.1020C>G	p.Phe340Leu	missense_variant	Exon 8 of 11		NP_001186759.1
HPSE	NM_001166498.3	c.984+3187C>G		intron_variant	Intron 8 of 10		NP_001159970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10	c.1194C>G	p.Phe398Leu	missense_variant	Exon 9 of 12	1	NM_001098540.3	ENSP00000308107.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1194C>G (p.F398L) alteration is located in exon 10 (coding exon 9) of the HPSE gene. This alteration results from a C to G substitution at nucleotide position 1194, causing the phenylalanine (F) at amino acid position 398 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	Pathogenic	0.58
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.2
DANN	Benign	0.94
DEOGEN2	Uncertain	0.44	T;T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.31	B;B;.
Vest4		0.42
MutPred		0.71		Gain of disorder (P = 0.194);Gain of disorder (P = 0.194);.;
MVP		0.16
MPC		0.14
ClinPred		0.55	D
GERP RS		-5.0
Varity_R		0.36
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-84227368;