rs41290587

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003118.4(SPARC):c.733G>A(p.Gly245Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00564 in 1,613,588 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G245E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0043 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 30 hom. )

Consequence

SPARC
NM_003118.4 missense, splice_region

Scores

Splicing: ADA: 0.0007721

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 7.35

Publications

17 publications found

Variant links:

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]

SPARC Gene-Disease associations (from GenCC):

osteogenesis imperfecta type 17
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
osteogenesis imperfecta type 4
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPARC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017677844).

BP6

Variant 5-151666362-C-T is Benign according to our data. Variant chr5-151666362-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 785151.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPARC	NM_003118.4 link	c.733G>A	p.Gly245Arg	missense_variant, splice_region_variant	Exon 8 of 10	ENST00000231061.9	NP_003109.1	P09486
SPARC	NM_001309444.2 link	c.733G>A	p.Gly245Arg	missense_variant, splice_region_variant	Exon 8 of 10		NP_001296373.1	P09486
SPARC	NM_001309443.2 link	c.730G>A	p.Gly244Arg	missense_variant, splice_region_variant	Exon 8 of 10		NP_001296372.1	P09486

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPARC	ENST00000231061.9 link	c.733G>A	p.Gly245Arg	missense_variant, splice_region_variant	Exon 8 of 10	1	NM_003118.4	ENSP00000231061.4		P09486

Frequencies

GnomAD3 genomes

AF:

0.00434

AC:

661

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00725

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00431

AC:

1080

AN:

250490

AF XY:

0.00436

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00501

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.00642

Gnomad OTH exome

AF:

0.00833

GnomAD4 exome

AF:

0.00578

AC:

8446

AN:

1461276

Hom.:

Cov.:

AF XY:

0.00573

AC XY:

4166

AN XY:

726940

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33474

American (AMR)

AF:

0.00537

AC:

240

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00134

AC:

AN:

26062

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.00239

AC:

206

AN:

86196

European-Finnish (FIN)

AF:

0.000936

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00644

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00669

AC:

7441

AN:

1111646

Other (OTH)

AF:

0.00663

AC:

400

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

393

786

1178

1571

1964

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

266

532

798

1064

1330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00433

AC:

660

AN:

152312

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41564

American (AMR)

AF:

0.00320

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00725

AC:

493

AN:

68028

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00550

Hom.:

Bravo

AF:

0.00414

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00451

AC:

548

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00726

EpiControl

AF:

0.00700

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPARC: BS2 -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 05, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Mar 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.733G>A (p.G245R) alteration is located in exon 8 (coding exon 7) of the SPARC gene. This alteration results from a G to A substitution at nucleotide position 733, causing the glycine (G) at amino acid position 245 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Osteogenesis imperfecta

Benign:1

Mar 29, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SPARC-related disorder

Benign:1

May 08, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Benign

0.093

DEOGEN2

Benign

0.17

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.032

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.047

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

PhyloP100

7.4

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

4.2

REVEL

Benign

0.28

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.36

Vest4

0.92

MutPred

0.59

Loss of helix (P = 0.0068);

MVP

0.37

MPC

0.76

ClinPred

0.043

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.43

gMVP

0.90

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00077

dbscSNV1_RF

Benign

0.088

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over