NM_003118.4:c.120+42T>C

Variant names:

• chr5-151674570-A-G
• rs2304051
• NM_003118.4:c.120+42T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003118.4(SPARC):​c.120+42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.094 in 1,591,912 control chromosomes in the GnomAD database, including 11,954 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4098 hom., cov: 32)
  • Exomes 𝑓: 0.086 (7856 hom.)
• Consequence: SPARC NM_003118.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.57
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-151674570-A-G is Benign according to our data. Variant chr5-151674570-A-G is described in ClinVar as Benign. ClinVar VariationId is 1296627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPARC	NM_003118.4	c.120+42T>C		intron_variant	Intron 3 of 9	ENST00000231061.9	NP_003109.1
SPARC	NM_001309444.2	c.120+42T>C		intron_variant	Intron 3 of 9		NP_001296373.1
SPARC	NM_001309443.2	c.117+42T>C		intron_variant	Intron 3 of 9		NP_001296372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPARC	ENST00000231061.9	c.120+42T>C		intron_variant	Intron 3 of 9	1	NM_003118.4	ENSP00000231061.4

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26176 AN: 151964 Hom.: 4077 Cov.: 32

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0889

Gnomad ASJ AF: 0.0893

Gnomad EAS AF: 0.0654

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0877

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0713

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.101 AC: 25236 AN: 249652 AF XY: 0.0981

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.0525

Gnomad ASJ exome AF: 0.0817

Gnomad EAS exome AF: 0.0660

Gnomad FIN exome AF: 0.0807

Gnomad NFE exome AF: 0.0712

Gnomad OTH exome AF: 0.0777

GnomAD4 exome AF: 0.0857 AC: 123408 AN: 1439830 Hom.: 7856 Cov.: 26 AF XY: 0.0868 AC XY: 62319 AN XY: 717820

African (AFR) AF: 0.438 AC: 14375 AN: 32816

American (AMR) AF: 0.0564 AC: 2506 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.0790 AC: 2047 AN: 25898

East Asian (EAS) AF: 0.0743 AC: 2943 AN: 39600

South Asian (SAS) AF: 0.138 AC: 11781 AN: 85630

European-Finnish (FIN) AF: 0.0798 AC: 4255 AN: 53338

Middle Eastern (MID) AF: 0.106 AC: 604 AN: 5718

European-Non Finnish (NFE) AF: 0.0723 AC: 79005 AN: 1092728

Other (OTH) AF: 0.0987 AC: 5892 AN: 59680

GnomAD4 genome AF: 0.173 AC: 26238 AN: 152082 Hom.: 4098 Cov.: 32 AF XY: 0.171 AC XY: 12703 AN XY: 74356

African (AFR) AF: 0.420 AC: 17407 AN: 41404

American (AMR) AF: 0.0887 AC: 1356 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0893 AC: 310 AN: 3470

East Asian (EAS) AF: 0.0650 AC: 337 AN: 5184

South Asian (SAS) AF: 0.139 AC: 668 AN: 4816

European-Finnish (FIN) AF: 0.0877 AC: 929 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0713 AC: 4850 AN: 68010

Other (OTH) AF: 0.153 AC: 324 AN: 2112

Alfa AF: 0.0640 Hom.: 146

Bravo AF: 0.183

Asia WGS AF: 0.114 AC: 400 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type 17 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.25
DANN	Benign	0.41
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2304051; hg19: chr5-151054131; COSMIC: COSV50558580; COSMIC: COSV50558580;