Genetic Variant SPARCL1:p.Gly547Val (chr4-87482452-C-A) – 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.1640G>T(p.Gly547Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,572 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: 0.0000055 ( 0 hom. )

Consequence

SPARCL1
NM_004684.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

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.1640G>T	p.Gly547Val	missense_variant	Exon 8 of 11	ENST00000282470.11	NP_004675.3	Q14515-1Q8N4S1
SPARCL1	NM_001128310.3 link	c.1640G>T	p.Gly547Val	missense_variant	Exon 9 of 12		NP_001121782.1	Q14515-1
SPARCL1	NM_001291976.2 link	c.1265G>T	p.Gly422Val	missense_variant	Exon 9 of 12		NP_001278905.1	Q14515-2B7ZB68
SPARCL1	NM_001291977.2 link	c.1265G>T	p.Gly422Val	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.1640G>T	p.Gly547Val	missense_variant	Exon 8 of 11	1	NM_004684.6	ENSP00000282470.6	Q14515-1
SPARCL1	ENST00000418378.5 link	c.1640G>T	p.Gly547Val	missense_variant	Exon 9 of 12	5		ENSP00000414856.1	Q14515-1
SPARCL1	ENST00000503414.5 link	c.1265G>T	p.Gly422Val	missense_variant	Exon 9 of 12	2		ENSP00000422903.1	Q14515-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251210

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135782

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:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461572

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727080

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:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1640G>T (p.G547V) alteration is located in exon 9 (coding exon 7) of the SPARCL1 gene. This alteration results from a G to T substitution at nucleotide position 1640, causing the glycine (G) at amino acid position 547 to be replaced by a valine (V). 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

Uncertain

0.37

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

T;T;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.0041

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.81

.;T;T

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.4

M;M;.

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.50

MutPred

0.66

Loss of disorder (P = 0.0236);Loss of disorder (P = 0.0236);.;

MVP

0.24

MPC

0.49

ClinPred

0.76

GERP RS

5.5

Varity_R

0.58

gMVP

0.81

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