4-87493595-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004684.6(SPARCL1):c.1205G>C(p.Gly402Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G402E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SPARCL1 NM_004684.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.263

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043014616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPARCL1	NM_004684.6	c.1205G>C	p.Gly402Ala	missense_variant	4/11	ENST00000282470.11
SPARCL1	NM_001128310.3	c.1205G>C	p.Gly402Ala	missense_variant	5/12
SPARCL1	NM_001291976.2	c.830G>C	p.Gly277Ala	missense_variant	5/12
SPARCL1	NM_001291977.2	c.830G>C	p.Gly277Ala	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPARCL1	ENST00000282470.11	c.1205G>C	p.Gly402Ala	missense_variant	4/11	1	NM_004684.6	P2
SPARCL1	ENST00000418378.5	c.1205G>C	p.Gly402Ala	missense_variant	5/12	5		P2
SPARCL1	ENST00000503414.5	c.830G>C	p.Gly277Ala	missense_variant	5/12	2		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455566 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723404

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2023

The c.1205G>C (p.G402A) alteration is located in exon 5 (coding exon 3) of the SPARCL1 gene. This alteration results from a G to C substitution at nucleotide position 1205, causing the glycine (G) at amino acid position 402 to be replaced by an alanine (A). 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	0.077
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.11
Dann	Benign	0.37
DEOGEN2	Benign	0.034	T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.026	N
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.75	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.79	T;T;T
Polyphen		0.0090	B;B;.
Vest4		0.046
MutPred		0.21		Loss of loop (P = 0.0031);Loss of loop (P = 0.0031);.;
MVP		0.27
MPC		0.087
ClinPred		0.047	T
GERP RS		-1.1
Varity_R		0.033
gMVP		0.16

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: rs764713722; hg19: chr4-88414747;