4-87493748-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004684.6(SPARCL1):c.1052A>C(p.Asp351Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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: 0.147

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15020964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPARCL1	NM_004684.6	c.1052A>C	p.Asp351Ala	missense_variant	4/11	ENST00000282470.11
SPARCL1	NM_001128310.3	c.1052A>C	p.Asp351Ala	missense_variant	5/12
SPARCL1	NM_001291976.2	c.677A>C	p.Asp226Ala	missense_variant	5/12
SPARCL1	NM_001291977.2	c.677A>C	p.Asp226Ala	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPARCL1	ENST00000282470.11	c.1052A>C	p.Asp351Ala	missense_variant	4/11	1	NM_004684.6	P2
SPARCL1	ENST00000418378.5	c.1052A>C	p.Asp351Ala	missense_variant	5/12	5		P2
SPARCL1	ENST00000503414.5	c.677A>C	p.Asp226Ala	missense_variant	5/12	2		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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.1052A>C (p.D351A) alteration is located in exon 5 (coding exon 3) of the SPARCL1 gene. This alteration results from a A to C substitution at nucleotide position 1052, causing the aspartic acid (D) at amino acid position 351 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	0.11
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	11
Dann	Benign	0.87
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.82	N;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.48	T;T;T
Polyphen		0.67	P;P;.
Vest4		0.12
MutPred		0.25		Gain of catalytic residue at D351 (P = 0.02);Gain of catalytic residue at D351 (P = 0.02);.;
MVP		0.44
MPC		0.26
ClinPred		0.26	T
GERP RS		0.046
Varity_R		0.077
gMVP		0.11

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.

Other links and lift over

hg19: chr4-88414900;