Genetic Variant SPARCL1:p.Ala49Asp (chr4-87495036-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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.

Frequency

Genomes: 𝑓 0.51 ( 22817 hom., cov: 33)

Exomes 𝑓: 0.39 ( 118054 hom. )

Consequence

SPARCL1
NM_004684.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.951

Publications

30 publications found

Variant links:

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

SPARCL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPARCL1	NM_004684.6 link	c.146C>A	p.Ala49Asp	missense_variant	Exon 3 of 11	ENST00000282470.11	NP_004675.3	Q14515-1Q8N4S1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPARCL1	ENST00000282470.11 link	c.146C>A	p.Ala49Asp	missense_variant	Exon 3 of 11	1	NM_004684.6	ENSP00000282470.6		Q14515-1

Frequencies

GnomAD3 genomes

AF:

0.513

AC:

77955

AN:

152022

Hom.:

22774

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.396

AC XY:

286965

AN XY:

724788

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

16808

33616

50424

67232

84040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12854

25708

38562

51416

64270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.513

AC:

78052

AN:

152140

Hom.:

22817

Cov.:

AF XY:

0.515

AC XY:

38305

AN XY:

74374

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1726

3453

5179

6906

8632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

654

1308

1962

2616

3270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.4

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.019

T;T;.;.;T;.;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.26

.;T;T;T;T;T;T;T

MetaRNN

Benign

9.2e-7

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.1

N;N;.;.;.;.;.;.

PhyloP100

0.95

PrimateAI

Benign

0.31

PROVEAN

Benign

1.4

N;N;N;N;N;N;N;N

REVEL

Benign

0.093

Sift

Benign

0.93

T;T;T;T;T;T;T;T

Sift4G

Benign

0.74

T;T;.;.;.;T;T;.

Polyphen

0.0

B;B;.;.;.;.;.;.

Vest4

0.038

MPC

0.12

ClinPred

0.00023

GERP RS

3.0

Varity_R

0.062

gMVP

0.085

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over