4-83309451-T-G

Variant names:

• chr4-83309451-T-G
• NM_001098540.3:c.935A>C

Variant summary

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

The NM_001098540.3(HPSE):​c.935A>C​(p.Asn312Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HPSE NM_001098540.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37

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=0.32425207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPSE	NM_001098540.3	c.935A>C	p.Asn312Thr	missense_variant	Exon 7 of 12	ENST00000311412.10	NP_001092010.1
HPSE	NM_006665.6	c.935A>C	p.Asn312Thr	missense_variant	Exon 8 of 13		NP_006656.2
HPSE	NM_001199830.1	c.761A>C	p.Asn254Thr	missense_variant	Exon 6 of 11		NP_001186759.1
HPSE	NM_001166498.3	c.935A>C	p.Asn312Thr	missense_variant	Exon 8 of 11		NP_001159970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10	c.935A>C	p.Asn312Thr	missense_variant	Exon 7 of 12	1	NM_001098540.3	ENSP00000308107.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441932 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 717976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.11e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T;.;.
Eigen	Benign	0.080
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	.;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;M;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.027	D;D;T;D
Sift4G	Uncertain	0.050	T;T;T;D
Polyphen		0.85	P;P;.;.
Vest4		0.24
MutPred		0.52		Gain of phosphorylation at N312 (P = 0.0635);Gain of phosphorylation at N312 (P = 0.0635);Gain of phosphorylation at N312 (P = 0.0635);.;
MVP		0.44
MPC		0.25
ClinPred		0.94	D
GERP RS		2.4
Varity_R		0.39
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-84230604;