rs41290587

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_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. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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:5

Conservation

PhyloP100: 7.35

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 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

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 id is 785151.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SPARC	NM_003118.4 linkuse as main transcript	c.733G>A	p.Gly245Arg	missense_variant, splice_region_variant	8/10	ENST00000231061.9
SPARC	NM_001309444.2 linkuse as main transcript	c.733G>A	p.Gly245Arg	missense_variant, splice_region_variant	8/10
SPARC	NM_001309443.2 linkuse as main transcript	c.730G>A	p.Gly244Arg	missense_variant, splice_region_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SPARC	ENST00000231061.9 linkuse as main transcript	c.733G>A	p.Gly245Arg	missense_variant, splice_region_variant	8/10	1	NM_003118.4	P1
SPARC	ENST00000520687.1 linkuse as main transcript	n.336G>A		splice_region_variant, non_coding_transcript_exon_variant	2/4	2
SPARC	ENST00000538026.5 linkuse as main transcript			downstream_gene_variant		5

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

GnomAD3 exomes

AF:

0.00431

AC:

1080

AN:

250490

Hom.:

AF XY:

0.00436

AC XY:

591

AN XY:

135430

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 SAS exome

AF:

0.00223

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

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00537

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00239

Gnomad4 FIN exome

AF:

0.000936

Gnomad4 NFE exome

AF:

0.00669

Gnomad4 OTH exome

AF:

0.00663

GnomAD4 genome

AF:

0.00433

AC:

660

AN:

152312

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00725

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00588

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:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	SPARC: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2021	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 29, 2022

- -

SPARC-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

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

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

MutationTaster

Benign

1.0

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over