4-87482558-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004684.6(SPARCL1):c.1534A>G(p.Ile512Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPARCL1 NM_004684.6 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.73

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3617589).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPARCL1	NM_004684.6	c.1534A>G	p.Ile512Val	missense_variant, splice_region_variant	8/11	ENST00000282470.11
SPARCL1	NM_001128310.3	c.1534A>G	p.Ile512Val	missense_variant, splice_region_variant	9/12
SPARCL1	NM_001291976.2	c.1159A>G	p.Ile387Val	missense_variant, splice_region_variant	9/12
SPARCL1	NM_001291977.2	c.1159A>G	p.Ile387Val	missense_variant, splice_region_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPARCL1	ENST00000282470.11	c.1534A>G	p.Ile512Val	missense_variant, splice_region_variant	8/11	1	NM_004684.6	P2
SPARCL1	ENST00000418378.5	c.1534A>G	p.Ile512Val	missense_variant, splice_region_variant	9/12	5		P2
SPARCL1	ENST00000503414.5	c.1159A>G	p.Ile387Val	missense_variant, splice_region_variant	9/12	2		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

May 31, 2023

The c.1534A>G (p.I512V) alteration is located in exon 9 (coding exon 7) of the SPARCL1 gene. This alteration results from a A to G substitution at nucleotide position 1534, causing the isoleucine (I) at amino acid position 512 to be replaced by a valine (V). 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.12	T;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.47
MutPred		0.51		Gain of ubiquitination at K510 (P = 0.1115);Gain of ubiquitination at K510 (P = 0.1115);.;
MVP		0.32
MPC		0.37
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.22
gMVP		0.43

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: chr4-88403710;