4-83309466-T-A

Position:

• chr4-83309466-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000311412.10(HPSE):​c.920A>T​(p.Lys307Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K307R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HPSE ENST00000311412.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.00

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25025275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPSE	NM_001098540.3	c.920A>T	p.Lys307Met	missense_variant	7/12	ENST00000311412.10	NP_001092010.1
HPSE	NM_006665.6	c.920A>T	p.Lys307Met	missense_variant	8/13		NP_006656.2
HPSE	NM_001199830.1	c.746A>T	p.Lys249Met	missense_variant	6/11		NP_001186759.1
HPSE	NM_001166498.3	c.920A>T	p.Lys307Met	missense_variant	8/11		NP_001159970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPSE	ENST00000311412.10	c.920A>T	p.Lys307Met	missense_variant	7/12	1	NM_001098540.3	ENSP00000308107	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1426252 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 710856

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.78	.;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.6	M;M;M;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.24	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.096	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.95	P;P;.;.
Vest4		0.38
MutPred		0.52		Loss of ubiquitination at K307 (P = 0.0063);Loss of ubiquitination at K307 (P = 0.0063);Loss of ubiquitination at K307 (P = 0.0063);.;
MVP		0.27
MPC		0.41
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.14
gMVP		0.52

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: rs11099592; hg19: chr4-84230619;