4-87480376-C-T

Variant names:

• chr4-87480376-C-T
• NM_004684.6:c.1813G>A

Variant summary

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

The NM_004684.6(SPARCL1):​c.1813G>A​(p.Asp605Asn) 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. 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: 7.53

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, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPARCL1	NM_004684.6	c.1813G>A	p.Asp605Asn	missense_variant	Exon 9 of 11	ENST00000282470.11	NP_004675.3
SPARCL1	NM_001128310.3	c.1813G>A	p.Asp605Asn	missense_variant	Exon 10 of 12		NP_001121782.1
SPARCL1	NM_001291976.2	c.1438G>A	p.Asp480Asn	missense_variant	Exon 10 of 12		NP_001278905.1
SPARCL1	NM_001291977.2	c.1438G>A	p.Asp480Asn	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.1813G>A	p.Asp605Asn	missense_variant	Exon 9 of 11	1	NM_004684.6	ENSP00000282470.6
SPARCL1	ENST00000418378.5	c.1813G>A	p.Asp605Asn	missense_variant	Exon 10 of 12	5		ENSP00000414856.1
SPARCL1	ENST00000503414.5	c.1438G>A	p.Asp480Asn	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

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1813G>A (p.D605N) alteration is located in exon 10 (coding exon 8) of the SPARCL1 gene. This alteration results from a G to A substitution at nucleotide position 1813, causing the aspartic acid (D) at amino acid position 605 to be replaced by an asparagine (N). 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	0.55
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.8	M;M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.91		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;
MVP		0.37
MPC		0.44
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.82
gMVP		0.81

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: chr4-88401528; COSMIC: COSV56805392;