NM_004684.6:c.146C>A

Variant names:

• chr4-87495036-G-T
• rs13051
• NM_004684.6:c.146C>A

Variant summary

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

The NM_004684.6(SPARCL1):​c.146C>A​(p.Ala49Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,608,716 control chromosomes in the GnomAD database, including 140,871 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A49G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.51 (22817 hom., cov: 33)
  • Exomes 𝑓: 0.39 (118054 hom.)
• Consequence: SPARCL1 NM_004684.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.951
• Publications: 30 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):

• corneal dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
• 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=9.185086E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004684.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPARCL1	NM_004684.6	MANE Select	c.146C>A	p.Ala49Asp	missense	Exon 3 of 11	NP_004675.3
	SPARCL1	NM_001291976.2		c.-230C>A		5_prime_UTR_premature_start_codon_gain	Exon 4 of 12	NP_001278905.1	Q14515-2
	SPARCL1	NM_001128310.3		c.146C>A	p.Ala49Asp	missense	Exon 4 of 12	NP_001121782.1	Q14515-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPARCL1	ENST00000282470.11	TSL:1 MANE Select	c.146C>A	p.Ala49Asp	missense	Exon 3 of 11	ENSP00000282470.6	Q14515-1
	SPARCL1	ENST00000503414.5	TSL:2	c.-230C>A		5_prime_UTR_premature_start_codon_gain	Exon 4 of 12	ENSP00000422903.1	Q14515-2
	SPARCL1	ENST00000541496.1	TSL:2	c.-230C>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 4	ENSP00000445678.1	F5H1Y9

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77955 AN: 152022 Hom.: 22774 Cov.: 33

Gnomad AFR AF: 0.805

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.572

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.491

GnomAD2 exomes AF: 0.449 AC: 112080 AN: 249676 AF XY: 0.444

Gnomad AFR exome AF: 0.820

Gnomad AMR exome AF: 0.498

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.430

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.368

Gnomad OTH exome AF: 0.417

GnomAD4 exome AF: 0.392 AC: 570514 AN: 1456576 Hom.: 118054 Cov.: 33 AF XY: 0.396 AC XY: 286965 AN XY: 724788

African (AFR) AF: 0.821 AC: 27350 AN: 33328

American (AMR) AF: 0.493 AC: 21847 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 11741 AN: 26078

East Asian (EAS) AF: 0.395 AC: 15627 AN: 39558

South Asian (SAS) AF: 0.562 AC: 48207 AN: 85724

European-Finnish (FIN) AF: 0.384 AC: 20492 AN: 53378

Middle Eastern (MID) AF: 0.512 AC: 2946 AN: 5756

European-Non Finnish (NFE) AF: 0.358 AC: 396527 AN: 1108252

Other (OTH) AF: 0.429 AC: 25777 AN: 60154

GnomAD4 genome AF: 0.513 AC: 78052 AN: 152140 Hom.: 22817 Cov.: 33 AF XY: 0.515 AC XY: 38305 AN XY: 74374

African (AFR) AF: 0.805 AC: 33419 AN: 41522

American (AMR) AF: 0.496 AC: 7582 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1568 AN: 3470

East Asian (EAS) AF: 0.422 AC: 2185 AN: 5174

South Asian (SAS) AF: 0.570 AC: 2754 AN: 4828

European-Finnish (FIN) AF: 0.395 AC: 4175 AN: 10558

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24594 AN: 67986

Other (OTH) AF: 0.495 AC: 1043 AN: 2106

Alfa AF: 0.417 Hom.: 31309

Bravo AF: 0.531

TwinsUK AF: 0.357 AC: 1325

ALSPAC AF: 0.357 AC: 1377

ESP6500AA AF: 0.807 AC: 3556

ESP6500EA AF: 0.372 AC: 3196

ExAC AF: 0.457 AC: 55427

Asia WGS AF: 0.567 AC: 1971 AN: 3478

EpiCase AF: 0.372

EpiControl AF: 0.370

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.4
DANN	Benign	0.17
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.95
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.093
Sift	Benign	0.93	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.038
MPC		0.12
ClinPred		0.00023	T
GERP RS		3.0
Varity_R		0.062
gMVP		0.085
Mutation Taster		=95/5	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: rs13051; hg19: chr4-88416188; COSMIC: COSV56802387;