Genetic Variant SPARCL1:p.Glu551Lys (chr4-87482441-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_004684.6(SPARCL1):c.1651G>A(p.Glu551Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,442 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SPARCL1
NM_004684.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.32

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 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 link	c.1651G>A	p.Glu551Lys	missense_variant	Exon 8 of 11	ENST00000282470.11	NP_004675.3	Q14515-1Q8N4S1
SPARCL1	NM_001128310.3 link	c.1651G>A	p.Glu551Lys	missense_variant	Exon 9 of 12		NP_001121782.1	Q14515-1
SPARCL1	NM_001291976.2 link	c.1276G>A	p.Glu426Lys	missense_variant	Exon 9 of 12		NP_001278905.1	Q14515-2B7ZB68
SPARCL1	NM_001291977.2 link	c.1276G>A	p.Glu426Lys	missense_variant	Exon 7 of 10		NP_001278906.1	Q14515-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPARCL1	ENST00000282470.11 link	c.1651G>A	p.Glu551Lys	missense_variant	Exon 8 of 11	1	NM_004684.6	ENSP00000282470.6	Q14515-1
SPARCL1	ENST00000418378.5 link	c.1651G>A	p.Glu551Lys	missense_variant	Exon 9 of 12	5		ENSP00000414856.1	Q14515-1
SPARCL1	ENST00000503414.5 link	c.1276G>A	p.Glu426Lys	missense_variant	Exon 9 of 12	2		ENSP00000422903.1	Q14515-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251086

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461442

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727024

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1651G>A (p.E551K) alteration is located in exon 9 (coding exon 7) of the SPARCL1 gene. This alteration results from a G to A substitution at nucleotide position 1651, causing the glutamic acid (E) at amino acid position 551 to be replaced by a lysine (K). 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

0.23

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

.;D;D

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.8

L;L;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.4

N;N;D

REVEL

Benign

0.21

Sift

Benign

0.042

D;D;T

Sift4G

Uncertain

0.056

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.27

MutPred

0.76

Gain of MoRF binding (P = 0.005);Gain of MoRF binding (P = 0.005);.;

MVP

0.39

MPC

0.46

ClinPred

0.92

GERP RS

5.5

Varity_R

0.27

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over