4-87479514-T-C

Variant names:

• chr4-87479514-T-C
• rs151251968
• NM_004684.6:c.1882A>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.1882A>G​(p.Thr628Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,614,066 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: SPARCL1 NM_004684.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

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=0.031567276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPARCL1	NM_004684.6	c.1882A>G	p.Thr628Ala	missense_variant	Exon 10 of 11	ENST00000282470.11	NP_004675.3
SPARCL1	NM_001128310.3	c.1882A>G	p.Thr628Ala	missense_variant	Exon 11 of 12		NP_001121782.1
SPARCL1	NM_001291976.2	c.1507A>G	p.Thr503Ala	missense_variant	Exon 11 of 12		NP_001278905.1
SPARCL1	NM_001291977.2	c.1507A>G	p.Thr503Ala	missense_variant	Exon 9 of 10		NP_001278906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPARCL1	ENST00000282470.11	c.1882A>G	p.Thr628Ala	missense_variant	Exon 10 of 11	1	NM_004684.6	ENSP00000282470.6
SPARCL1	ENST00000418378.5	c.1882A>G	p.Thr628Ala	missense_variant	Exon 11 of 12	5		ENSP00000414856.1
SPARCL1	ENST00000503414.5	c.1507A>G	p.Thr503Ala	missense_variant	Exon 11 of 12	2		ENSP00000422903.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000406 AC: 102 AN: 251464 Hom.: 0 AF XY: 0.000530 AC XY: 72 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000281

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000226 AC: 330 AN: 1461860 Hom.: 1 Cov.: 31 AF XY: 0.000286 AC XY: 208 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000107

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74414

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000494 AC: 60

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1882A>G (p.T628A) alteration is located in exon 11 (coding exon 9) of the SPARCL1 gene. This alteration results from a A to G substitution at nucleotide position 1882, causing the threonine (T) at amino acid position 628 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	0.31
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.032	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.2	N;N;D
REVEL	Benign	0.15
Sift	Benign	0.11	T;T;T
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.59
MVP		0.39
MPC		0.42
ClinPred		0.053	T
GERP RS		5.1
Varity_R		0.24
gMVP		0.53

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: rs151251968; hg19: chr4-88400666;