rs1057517662
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_003118.4(SPARC):c.497G>A(p.Arg166His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
SPARC
NM_003118.4 missense
NM_003118.4 missense
Scores
13
4
2
Clinical Significance
Conservation
PhyloP100: 7.35
Genes affected
SPARC (HGNC:11219): (secreted protein acidic and cysteine rich) This gene encodes a cysteine-rich acidic matrix-associated protein. The encoded protein is required for the collagen in bone to become calcified but is also involved in extracellular matrix synthesis and promotion of changes to cell shape. The gene product has been associated with tumor suppression but has also been correlated with metastasis based on changes to cell shape which can promote tumor cell invasion. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a disulfide_bond (size 110) in uniprot entity SPRC_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_003118.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.962
PP5
?
Variant 5-151667555-C-T is Pathogenic according to our data. Variant chr5-151667555-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 372140.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-151667555-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPARC | NM_003118.4 | c.497G>A | p.Arg166His | missense_variant | 7/10 | ENST00000231061.9 | |
SPARC | NM_001309444.2 | c.497G>A | p.Arg166His | missense_variant | 7/10 | ||
SPARC | NM_001309443.2 | c.494G>A | p.Arg165His | missense_variant | 7/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPARC | ENST00000231061.9 | c.497G>A | p.Arg166His | missense_variant | 7/10 | 1 | NM_003118.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251318Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135832
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727234
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74332
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type 17 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 19, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;.;D
Polyphen
D;.;.
Vest4
MutPred
Loss of sheet (P = 0.0457);.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at