rs2066522

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014140.4(SMARCAL1):c.945C>G(p.Ser315Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,614,134 control chromosomes in the GnomAD database, including 884 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.041 ( 189 hom., cov: 32)

Exomes 𝑓: 0.028 ( 695 hom. )

Consequence

SMARCAL1
NM_014140.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.682

Publications

11 publications found

Variant links:

Genes affected

SMARCAL1 (HGNC:11102): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a like 1) The protein encoded by this gene is a member of the SWI/SNF family of proteins. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein shows sequence similarity to the E. coli RNA polymerase-binding protein HepA. Mutations in this gene are a cause of Schimke immunoosseous dysplasia (SIOD), an autosomal recessive disorder with the diagnostic features of spondyloepiphyseal dysplasia, renal dysfunction, and T-cell immunodeficiency. [provided by RefSeq, Jul 2008]

SMARCAL1 Gene-Disease associations (from GenCC):

Schimke immuno-osseous dysplasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

SMARCAL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018854737).

BP6

Variant 2-216420381-C-G is Benign according to our data. Variant chr2-216420381-C-G is described in ClinVar as Benign. ClinVar VariationId is 197799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCAL1	NM_014140.4 link	c.945C>G	p.Ser315Arg	missense_variant	Exon 5 of 18	ENST00000357276.9	NP_054859.2	Q9NZC9
SMARCAL1	NM_001127207.2 link	c.945C>G	p.Ser315Arg	missense_variant	Exon 5 of 18		NP_001120679.1	Q9NZC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCAL1	ENST00000357276.9 link	c.945C>G	p.Ser315Arg	missense_variant	Exon 5 of 18	2	NM_014140.4	ENSP00000349823.4		Q9NZC9

Frequencies

GnomAD3 genomes

AF:

0.0411

AC:

6250

AN:

152170

Hom.:

187

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0807

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0343

Gnomad ASJ

AF:

0.0204

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00890

Gnomad FIN

AF:

0.0138

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0296

Gnomad OTH

AF:

0.0401

GnomAD2 exomes

AF:

0.0248

AC:

6240

AN:

251388

AF XY:

0.0238

show subpopulations

Gnomad AFR exome

AF:

0.0842

Gnomad AMR exome

AF:

0.0175

Gnomad ASJ exome

AF:

0.0240

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0162

Gnomad NFE exome

AF:

0.0281

Gnomad OTH exome

AF:

0.0333

GnomAD4 exome

AF:

0.0278

AC:

40712

AN:

1461846

Hom.:

695

Cov.:

AF XY:

0.0272

AC XY:

19809

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0864

AC:

2891

AN:

33478

American (AMR)

AF:

0.0211

AC:

942

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

648

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.00881

AC:

760

AN:

86258

European-Finnish (FIN)

AF:

0.0160

AC:

854

AN:

53420

Middle Eastern (MID)

AF:

0.0666

AC:

384

AN:

5768

European-Non Finnish (NFE)

AF:

0.0290

AC:

32297

AN:

1111970

Other (OTH)

AF:

0.0320

AC:

1930

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2281

4562

6844

9125

11406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1260

2520

3780

5040

6300

<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:

0.0411

AC:

6258

AN:

152288

Hom.:

189

Cov.:

AF XY:

0.0397

AC XY:

2954

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0808

AC:

3357

AN:

41556

American (AMR)

AF:

0.0342

AC:

523

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0204

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00912

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0138

AC:

146

AN:

10612

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0296

AC:

2014

AN:

68026

Other (OTH)

AF:

0.0392

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

305

611

916

1222

1527

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0292

Hom.:

Bravo

AF:

0.0442

TwinsUK

AF:

0.0310

AC:

115

ALSPAC

AF:

0.0304

AC:

117

ESP6500AA

AF:

0.0801

AC:

353

ESP6500EA

AF:

0.0290

AC:

249

ExAC

AF:

0.0257

AC:

3118

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0309

EpiControl

AF:

0.0304

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Schimke immuno-osseous dysplasia

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Focal segmental glomerulosclerosis

Benign:1

Aug 08, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.017

T;T;T;T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.61

.;T;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.8

L;L;.;.;.

PhyloP100

0.68

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.54

N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.19

T;T;D;T;T

Sift4G

Benign

0.49

T;T;T;T;T

Polyphen

0.80

P;P;.;.;.

Vest4

0.075

MutPred

0.096

Loss of glycosylation at S315 (P = 0.0138);Loss of glycosylation at S315 (P = 0.0138);.;.;.;

MPC

0.25

ClinPred

0.0068

GERP RS

-0.19

Varity_R

0.034

gMVP

0.25

Mutation Taster

=99/1

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over