4-87491654-T-C

Variant names:

• chr4-87491654-T-C
• rs1130643
• NM_004684.6:c.1255A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004684.6(SPARCL1):​c.1255A>G​(p.Thr419Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,611,944 control chromosomes in the GnomAD database, including 20,438 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (5230 hom., cov: 32)
  • Exomes 𝑓: 0.13 (15208 hom.)
• Consequence: SPARCL1 NM_004684.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.251
• Publications: 26 publications found

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 Gene-Disease associations (from GenCC):

• stromal corneal dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.8204918E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPARCL1	NM_004684.6	c.1255A>G	p.Thr419Ala	missense_variant	Exon 5 of 11	ENST00000282470.11	NP_004675.3
SPARCL1	NM_001128310.3	c.1255A>G	p.Thr419Ala	missense_variant	Exon 6 of 12		NP_001121782.1
SPARCL1	NM_001291976.2	c.880A>G	p.Thr294Ala	missense_variant	Exon 6 of 12		NP_001278905.1
SPARCL1	NM_001291977.2	c.880A>G	p.Thr294Ala	missense_variant	Exon 4 of 10		NP_001278906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPARCL1	ENST00000282470.11	c.1255A>G	p.Thr419Ala	missense_variant	Exon 5 of 11	1	NM_004684.6	ENSP00000282470.6
SPARCL1	ENST00000418378.5	c.1255A>G	p.Thr419Ala	missense_variant	Exon 6 of 12	5		ENSP00000414856.1
SPARCL1	ENST00000503414.5	c.880A>G	p.Thr294Ala	missense_variant	Exon 6 of 12	2		ENSP00000422903.1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32458 AN: 152038 Hom.: 5222 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.0755

Gnomad FIN AF: 0.0996

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.136 AC: 34181 AN: 251302 AF XY: 0.127

Gnomad AFR exome AF: 0.469

Gnomad AMR exome AF: 0.0833

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.158

Gnomad FIN exome AF: 0.0957

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.132 AC: 193274 AN: 1459788 Hom.: 15208 Cov.: 31 AF XY: 0.129 AC XY: 93943 AN XY: 726360

African (AFR) AF: 0.459 AC: 15320 AN: 33384

American (AMR) AF: 0.0902 AC: 4034 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3724 AN: 26116

East Asian (EAS) AF: 0.126 AC: 5008 AN: 39674

South Asian (SAS) AF: 0.0700 AC: 6033 AN: 86242

European-Finnish (FIN) AF: 0.0993 AC: 5293 AN: 53326

Middle Eastern (MID) AF: 0.126 AC: 725 AN: 5768

European-Non Finnish (NFE) AF: 0.130 AC: 144178 AN: 1110250

Other (OTH) AF: 0.149 AC: 8959 AN: 60312

GnomAD4 genome AF: 0.214 AC: 32493 AN: 152156 Hom.: 5230 Cov.: 32 AF XY: 0.209 AC XY: 15559 AN XY: 74418

African (AFR) AF: 0.453 AC: 18782 AN: 41470

American (AMR) AF: 0.138 AC: 2107 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 476 AN: 3470

East Asian (EAS) AF: 0.152 AC: 787 AN: 5172

South Asian (SAS) AF: 0.0745 AC: 360 AN: 4830

European-Finnish (FIN) AF: 0.0996 AC: 1057 AN: 10610

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8347 AN: 67994

Other (OTH) AF: 0.185 AC: 391 AN: 2112

Alfa AF: 0.155 Hom.: 6615

Bravo AF: 0.229

TwinsUK AF: 0.127 AC: 472

ALSPAC AF: 0.130 AC: 501

ESP6500AA AF: 0.453 AC: 1998

ESP6500EA AF: 0.130 AC: 1118

ExAC AF: 0.144 AC: 17453

Asia WGS AF: 0.160 AC: 558 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.121

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.29
DANN	Benign	0.32
DEOGEN2	Benign	0.045	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.27	.;T;T
MetaRNN	Benign	0.00028	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.52	N;N;.
PhyloP100		-0.25
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.50	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.021
MPC		0.075
ClinPred		0.00095	T
GERP RS		-4.3
Varity_R		0.030
gMVP		0.19
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1130643; hg19: chr4-88412806; COSMIC: COSV56803313; COSMIC: COSV56803313;