Variant 4-87490335-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004684.6(SPARCL1):c.1469G>A(p.Cys490Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,192 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SPARCL1
NM_004684.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SPARCL1	NM_004684.6 linkuse as main transcript	c.1469G>A	p.Cys490Tyr	missense_variant	7/11	ENST00000282470.11	NP_004675.3
SPARCL1	NM_001128310.3 linkuse as main transcript	c.1469G>A	p.Cys490Tyr	missense_variant	8/12		NP_001121782.1
SPARCL1	NM_001291976.2 linkuse as main transcript	c.1094G>A	p.Cys365Tyr	missense_variant	8/12		NP_001278905.1
SPARCL1	NM_001291977.2 linkuse as main transcript	c.1094G>A	p.Cys365Tyr	missense_variant	6/10		NP_001278906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPARCL1	ENST00000282470.11 linkuse as main transcript	c.1469G>A	p.Cys490Tyr	missense_variant	7/11	1	NM_004684.6	ENSP00000282470	P2	Q14515-1
SPARCL1	ENST00000418378.5 linkuse as main transcript	c.1469G>A	p.Cys490Tyr	missense_variant	8/12	5		ENSP00000414856	P2	Q14515-1
SPARCL1	ENST00000503414.5 linkuse as main transcript	c.1094G>A	p.Cys365Tyr	missense_variant	8/12	2		ENSP00000422903	A2	Q14515-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461192

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726858

show subpopulations

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.1469G>A (p.C490Y) alteration is located in exon 8 (coding exon 6) of the SPARCL1 gene. This alteration results from a G to A substitution at nucleotide position 1469, causing the cysteine (C) at amino acid position 490 to be replaced by a tyrosine (Y). 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

0.99

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.7

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-11

D;D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.94

MutPred

0.82

Loss of methylation at K489 (P = 0.03);Loss of methylation at K489 (P = 0.03);.;

MVP

0.94

MPC

0.57

ClinPred

1.0

GERP RS

4.6

Varity_R

0.95

gMVP

0.98

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over