4-87490351-G-T

Variant names:

• chr4-87490351-G-T
• NM_004684.6:c.1453C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

SPARCL1 Gene-Disease associations (from GenCC):

• corneal dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• stromal corneal dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004684.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPARCL1	NM_004684.6	MANE Select	c.1453C>A	p.Leu485Ile	missense	Exon 7 of 11	NP_004675.3
	SPARCL1	NM_001128310.3		c.1453C>A	p.Leu485Ile	missense	Exon 8 of 12	NP_001121782.1	Q14515-1
	SPARCL1	NM_001291976.2		c.1078C>A	p.Leu360Ile	missense	Exon 8 of 12	NP_001278905.1	Q14515-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPARCL1	ENST00000282470.11	TSL:1 MANE Select	c.1453C>A	p.Leu485Ile	missense	Exon 7 of 11	ENSP00000282470.6	Q14515-1
	SPARCL1	ENST00000946054.1		c.1453C>A	p.Leu485Ile	missense	Exon 7 of 11	ENSP00000616113.1
	SPARCL1	ENST00000880794.1		c.1453C>A	p.Leu485Ile	missense	Exon 7 of 11	ENSP00000550853.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.70		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
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

hg19: chr4-88411503;