rs41290587

Variant names:

• chr5-151666362-C-T
• rs41290587
• NM_003118.4:c.733G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001309444.2(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_001309444.2 missense, splice_region
• Scores: Splicing: ADA: 0.0007721
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 7.35
• Publications: 17 publications found

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

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001309444.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPARC	NM_003118.4	MANE Select	c.733G>A	p.Gly245Arg	missense splice_region	Exon 8 of 10	NP_003109.1
	SPARC	NM_001309444.2		c.733G>A	p.Gly245Arg	missense splice_region	Exon 8 of 10	NP_001296373.1
	SPARC	NM_001309443.2		c.730G>A	p.Gly244Arg	missense splice_region	Exon 8 of 10	NP_001296372.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPARC	ENST00000231061.9	TSL:1 MANE Select	c.733G>A	p.Gly245Arg	missense splice_region	Exon 8 of 10	ENSP00000231061.4
	SPARC	ENST00000896427.1		c.733G>A	p.Gly245Arg	missense splice_region	Exon 9 of 11	ENSP00000566486.1
	SPARC	ENST00000896428.1		c.733G>A	p.Gly245Arg	missense splice_region	Exon 8 of 10	ENSP00000566487.1

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 661 AN: 152196 Hom.: 3 Cov.: 33

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

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.: 30 Cov.: 31 AF XY: 0.00573 AC XY: 4166 AN XY: 726940

African (AFR) AF: 0.00108 AC: 36 AN: 33474

American (AMR) AF: 0.00537 AC: 240 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26062

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00239 AC: 206 AN: 86196

European-Finnish (FIN) AF: 0.000936 AC: 50 AN: 53398

Middle Eastern (MID) AF: 0.00644 AC: 37 AN: 5746

European-Non Finnish (NFE) AF: 0.00669 AC: 7441 AN: 1111646

Other (OTH) AF: 0.00663 AC: 400 AN: 60370

GnomAD4 genome AF: 0.00433 AC: 660 AN: 152312 Hom.: 3 Cov.: 33 AF XY: 0.00396 AC XY: 295 AN XY: 74470

African (AFR) AF: 0.00159 AC: 66 AN: 41564

American (AMR) AF: 0.00320 AC: 49 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00725 AC: 493 AN: 68028

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00550 Hom.: 10

Bravo AF: 0.00414

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00451 AC: 548

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00726

EpiControl AF: 0.00700

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	-	Inborn genetic diseases (1)
-	-	1	Osteogenesis imperfecta (1)
-	-	1	SPARC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Benign	0.093
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.032
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		7.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	4.2	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.36	B
Vest4		0.92
MutPred		0.59		Loss of helix (P = 0.0068)
MVP		0.37
MPC		0.76
ClinPred		0.043	T
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

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

Other links and lift over

dbSNP: rs41290587; hg19: chr5-151045923; COSMIC: COSV50558513; COSMIC: COSV50558513;