4-87480493-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004684.6(SPARCL1):c.1696A>G(p.Arg566Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPARCL1 NM_004684.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33

Genes affected

SPARCL1 (HGNC:11220): (SPARC like 1) Predicted to enable calcium ion binding activity; collagen binding activity; and extracellular matrix binding activity. Predicted to be involved in anatomical structure development and regulation of synapse organization. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPARCL1	NM_004684.6	c.1696A>G	p.Arg566Gly	missense_variant	9/11	ENST00000282470.11
SPARCL1	NM_001128310.3	c.1696A>G	p.Arg566Gly	missense_variant	10/12
SPARCL1	NM_001291976.2	c.1321A>G	p.Arg441Gly	missense_variant	10/12
SPARCL1	NM_001291977.2	c.1321A>G	p.Arg441Gly	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPARCL1	ENST00000282470.11	c.1696A>G	p.Arg566Gly	missense_variant	9/11	1	NM_004684.6	P2
SPARCL1	ENST00000418378.5	c.1696A>G	p.Arg566Gly	missense_variant	10/12	5		P2
SPARCL1	ENST00000503414.5	c.1321A>G	p.Arg441Gly	missense_variant	10/12	2		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458414 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725404

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

The c.1696A>G (p.R566G) alteration is located in exon 10 (coding exon 8) of the SPARCL1 gene. This alteration results from a A to G substitution at nucleotide position 1696, causing the arginine (R) at amino acid position 566 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.91
MutPred		0.86		Loss of MoRF binding (P = 0.0298);Loss of MoRF binding (P = 0.0298);.;
MVP		0.23
MPC		0.50
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.76
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-88401645;