rs2304052

Variant names:

• chr5-151674666-T-C
• rs2304052
• NM_003118.4:c.66A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003118.4(SPARC):​c.66A>G​(p.Glu22Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0942 in 1,613,444 control chromosomes in the GnomAD database, including 12,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4106 hom., cov: 32)
  • Exomes 𝑓: 0.086 (8017 hom.)
• Consequence: SPARC NM_003118.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0140
• Publications: 29 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, Ambry Genetics, PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 5-151674666-T-C is Benign according to our data. Variant chr5-151674666-T-C is described in ClinVar as Benign. ClinVar VariationId is 1287045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.014 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003118.4. 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.66A>G	p.Glu22Glu	synonymous	Exon 3 of 10	NP_003109.1	P09486
	SPARC	NM_001309444.2		c.66A>G	p.Glu22Glu	synonymous	Exon 3 of 10	NP_001296373.1
	SPARC	NM_001309443.2		c.63A>G	p.Glu21Glu	synonymous	Exon 3 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.66A>G	p.Glu22Glu	synonymous	Exon 3 of 10	ENSP00000231061.4	P09486
	SPARC	ENST00000896427.1		c.66A>G	p.Glu22Glu	synonymous	Exon 4 of 11	ENSP00000566486.1
	SPARC	ENST00000896428.1		c.66A>G	p.Glu22Glu	synonymous	Exon 3 of 10	ENSP00000566487.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26219 AN: 152036 Hom.: 4085 Cov.: 32

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0890

Gnomad ASJ AF: 0.0896

Gnomad EAS AF: 0.0649

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0881

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.153

GnomAD2 exomes AF: 0.101 AC: 25390 AN: 251106 AF XY: 0.0982

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.0527

Gnomad ASJ exome AF: 0.0816

Gnomad EAS exome AF: 0.0660

Gnomad FIN exome AF: 0.0811

Gnomad NFE exome AF: 0.0713

Gnomad OTH exome AF: 0.0773

GnomAD4 exome AF: 0.0861 AC: 125767 AN: 1461290 Hom.: 8017 Cov.: 31 AF XY: 0.0871 AC XY: 63302 AN XY: 726944

African (AFR) AF: 0.439 AC: 14685 AN: 33438

American (AMR) AF: 0.0565 AC: 2526 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0791 AC: 2068 AN: 26128

East Asian (EAS) AF: 0.0742 AC: 2947 AN: 39692

South Asian (SAS) AF: 0.138 AC: 11893 AN: 86218

European-Finnish (FIN) AF: 0.0800 AC: 4271 AN: 53406

Middle Eastern (MID) AF: 0.105 AC: 608 AN: 5768

European-Non Finnish (NFE) AF: 0.0727 AC: 80794 AN: 1111564

Other (OTH) AF: 0.0990 AC: 5975 AN: 60364

GnomAD4 genome AF: 0.173 AC: 26281 AN: 152154 Hom.: 4106 Cov.: 32 AF XY: 0.171 AC XY: 12719 AN XY: 74378

African (AFR) AF: 0.421 AC: 17441 AN: 41458

American (AMR) AF: 0.0887 AC: 1358 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0896 AC: 311 AN: 3470

East Asian (EAS) AF: 0.0645 AC: 333 AN: 5164

South Asian (SAS) AF: 0.139 AC: 669 AN: 4820

European-Finnish (FIN) AF: 0.0881 AC: 934 AN: 10598

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0713 AC: 4853 AN: 68020

Other (OTH) AF: 0.154 AC: 325 AN: 2112

Alfa AF: 0.110 Hom.: 5257

Bravo AF: 0.183

Asia WGS AF: 0.114 AC: 400 AN: 3478

EpiCase AF: 0.0747

EpiControl AF: 0.0754

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Osteogenesis imperfecta type 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.80
PhyloP100		0.014
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs2304052; hg19: chr5-151054227; COSMIC: COSV50558598; COSMIC: COSV50558598;