4-87490771-G-A

Variant names:

• chr4-87490771-G-A
• rs1724290647
• NM_004684.6:c.1399C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004684.6(SPARCL1):​c.1399C>T​(p.Pro467Ser) 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 benign outcome for this variant. 16/21 in silico tools predict a benign 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: 2.64

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057431012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPARCL1	NM_004684.6	c.1399C>T	p.Pro467Ser	missense_variant	Exon 6 of 11	ENST00000282470.11	NP_004675.3
SPARCL1	NM_001128310.3	c.1399C>T	p.Pro467Ser	missense_variant	Exon 7 of 12		NP_001121782.1
SPARCL1	NM_001291976.2	c.1024C>T	p.Pro342Ser	missense_variant	Exon 7 of 12		NP_001278905.1
SPARCL1	NM_001291977.2	c.1024C>T	p.Pro342Ser	missense_variant	Exon 5 of 10		NP_001278906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPARCL1	ENST00000282470.11	c.1399C>T	p.Pro467Ser	missense_variant	Exon 6 of 11	1	NM_004684.6	ENSP00000282470.6
SPARCL1	ENST00000418378.5	c.1399C>T	p.Pro467Ser	missense_variant	Exon 7 of 12	5		ENSP00000414856.1
SPARCL1	ENST00000503414.5	c.1024C>T	p.Pro342Ser	missense_variant	Exon 7 of 12	2		ENSP00000422903.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1399C>T (p.P467S) alteration is located in exon 7 (coding exon 5) of the SPARCL1 gene. This alteration results from a C to T substitution at nucleotide position 1399, causing the proline (P) at amino acid position 467 to be replaced by a serine (S). 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	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.49
DEOGEN2	Benign	0.077	T;T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.28	.;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.057	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.24	N;N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.059
Sift	Benign	0.85	T;T;T
Sift4G	Benign	0.68	T;T;T
Polyphen		0.074	B;B;.
Vest4		0.064
MutPred		0.26		Loss of methylation at K466 (P = 0.0704);Loss of methylation at K466 (P = 0.0704);.;
MVP		0.46
MPC		0.091
ClinPred		0.12	T
GERP RS		3.4
Varity_R		0.041
gMVP		0.20

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

LitVar

Other links and lift over

dbSNP: rs1724290647; hg19: chr4-88411923;