4-87490351-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004684.6(SPARCL1):c.1453C>A(p.Leu485Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPARCL1 NM_004684.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPARCL1	NM_004684.6	c.1453C>A	p.Leu485Ile	missense_variant	7/11	ENST00000282470.11
SPARCL1	NM_001128310.3	c.1453C>A	p.Leu485Ile	missense_variant	8/12
SPARCL1	NM_001291976.2	c.1078C>A	p.Leu360Ile	missense_variant	8/12
SPARCL1	NM_001291977.2	c.1078C>A	p.Leu360Ile	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPARCL1	ENST00000282470.11	c.1453C>A	p.Leu485Ile	missense_variant	7/11	1	NM_004684.6	P2
SPARCL1	ENST00000418378.5	c.1453C>A	p.Leu485Ile	missense_variant	8/12	5		P2
SPARCL1	ENST00000503414.5	c.1078C>A	p.Leu360Ile	missense_variant	8/12	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

Jun 02, 2023

The c.1453C>A (p.L485I) alteration is located in exon 8 (coding exon 6) of the SPARCL1 gene. This alteration results from a C to A substitution at nucleotide position 1453, causing the leucine (L) at amino acid position 485 to be replaced by an isoleucine (I). 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	0.45
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.57
MutPred		0.70		Gain of methylation at K489 (P = 0.0506);Gain of methylation at K489 (P = 0.0506);.;
MVP		0.77
MPC		0.46
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.29
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr4-88411503;