Genetic Variant NM_003118.4:c.*953T>G (chr5-151662618-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003118.4(SPARC):c.*953T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,688 control chromosomes in the GnomAD database, including 2,120 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 2115 hom., cov: 33)

Exomes 𝑓: 0.14 ( 5 hom. )

Consequence

SPARC
NM_003118.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.359

Publications

7 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SPARC	NM_003118.4 link	c.*953T>G	3_prime_UTR_variant	Exon 10 of 10	ENST00000231061.9	NP_003109.1	P09486
SPARC	NM_001309444.2 link	c.*837T>G	3_prime_UTR_variant	Exon 10 of 10		NP_001296373.1	P09486
SPARC	NM_001309443.2 link	c.*953T>G	3_prime_UTR_variant	Exon 10 of 10		NP_001296372.1	P09486

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPARC	ENST00000231061.9 link	c.*953T>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_003118.4	ENSP00000231061.4		P09486
SPARC	ENST00000520687.1 link	n.1468T>G		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.142

AC:

21561

AN:

152138

Hom.:

2112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0482

Gnomad AMI

AF:

0.121

Gnomad AMR

AF:

0.285

Gnomad ASJ

AF:

0.146

Gnomad EAS

AF:

0.380

Gnomad SAS

AF:

0.214

Gnomad FIN

AF:

0.148

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.152

GnomAD4 exome

AF:

0.141

AC:

AN:

432

Hom.:

Cov.:

AF XY:

0.163

AC XY:

AN XY:

258

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.142

AC:

AN:

424

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.250

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.142

AC:

21579

AN:

152256

Hom.:

2115

Cov.:

AF XY:

0.148

AC XY:

10988

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0481

AC:

1998

AN:

41552

American (AMR)

AF:

0.285

AC:

4365

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.146

AC:

506

AN:

3470

East Asian (EAS)

AF:

0.381

AC:

1972

AN:

5182

South Asian (SAS)

AF:

0.215

AC:

1034

AN:

4818

European-Finnish (FIN)

AF:

0.148

AC:

1567

AN:

10600

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.142

AC:

9640

AN:

68010

Other (OTH)

AF:

0.155

AC:

328

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

904

1808

2713

3617

4521

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<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:

0.137

Hom.:

816

Bravo

AF:

0.147

Asia WGS

AF:

0.296

AC:

1026

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.0

(source)

DANN

Benign

0.68

PhyloP100

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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

Computational scores

Splicing

Publications

Other links and lift over