4-87480381-G-A

Variant names:

• chr4-87480381-G-A
• NM_004684.6:c.1808C>T

Variant summary

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

The NM_004684.6(SPARCL1):​c.1808C>T​(p.Pro603Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPARCL1 NM_004684.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.55

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, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPARCL1	NM_004684.6	c.1808C>T	p.Pro603Leu	missense_variant	Exon 9 of 11	ENST00000282470.11	NP_004675.3
SPARCL1	NM_001128310.3	c.1808C>T	p.Pro603Leu	missense_variant	Exon 10 of 12		NP_001121782.1
SPARCL1	NM_001291976.2	c.1433C>T	p.Pro478Leu	missense_variant	Exon 10 of 12		NP_001278905.1
SPARCL1	NM_001291977.2	c.1433C>T	p.Pro478Leu	missense_variant	Exon 8 of 10		NP_001278906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPARCL1	ENST00000282470.11	c.1808C>T	p.Pro603Leu	missense_variant	Exon 9 of 11	1	NM_004684.6	ENSP00000282470.6
SPARCL1	ENST00000418378.5	c.1808C>T	p.Pro603Leu	missense_variant	Exon 10 of 12	5		ENSP00000414856.1
SPARCL1	ENST00000503414.5	c.1433C>T	p.Pro478Leu	missense_variant	Exon 10 of 12	2		ENSP00000422903.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1808C>T (p.P603L) alteration is located in exon 10 (coding exon 8) of the SPARCL1 gene. This alteration results from a C to T substitution at nucleotide position 1808, causing the proline (P) at amino acid position 603 to be replaced by a leucine (L). 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	0.90
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	.;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.1	M;M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-10	D;D;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.87		Loss of disorder (P = 0.0292);Loss of disorder (P = 0.0292);.;
MVP		0.54
MPC		0.45
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.78

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: chr4-88401533;