chr4-87479535-C-A

Variant names:

• chr4-87479535-C-A
• rs1723720906
• NM_004684.6:c.1861G>T

Variant summary

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

The NM_004684.6(SPARCL1):​c.1861G>T​(p.Val621Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPARCL1 NM_004684.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.815

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 rank	MANE	Protein	UniProt
SPARCL1	NM_004684.6	c.1861G>T	p.Val621Leu	missense_variant	Exon 10 of 11	ENST00000282470.11	NP_004675.3
SPARCL1	NM_001128310.3	c.1861G>T	p.Val621Leu	missense_variant	Exon 11 of 12		NP_001121782.1
SPARCL1	NM_001291976.2	c.1486G>T	p.Val496Leu	missense_variant	Exon 11 of 12		NP_001278905.1
SPARCL1	NM_001291977.2	c.1486G>T	p.Val496Leu	missense_variant	Exon 9 of 10		NP_001278906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPARCL1	ENST00000282470.11	c.1861G>T	p.Val621Leu	missense_variant	Exon 10 of 11	1	NM_004684.6	ENSP00000282470.6
SPARCL1	ENST00000418378.5	c.1861G>T	p.Val621Leu	missense_variant	Exon 11 of 12	5		ENSP00000414856.1
SPARCL1	ENST00000503414.5	c.1486G>T	p.Val496Leu	missense_variant	Exon 11 of 12	2		ENSP00000422903.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1861G>T (p.V621L) alteration is located in exon 11 (coding exon 9) of the SPARCL1 gene. This alteration results from a G to T substitution at nucleotide position 1861, causing the valine (V) at amino acid position 621 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	0.77
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.035	D;D;T
Sift4G	Uncertain	0.011	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.47
MutPred		0.66		Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);.;
MVP		0.40
MPC		0.44
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.32
gMVP		0.69

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: rs1723720906; hg19: chr4-88400687;