rs2066518

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_014140.4(SMARCAL1):c.1129G>C(p.Glu377Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0198 in 1,613,744 control chromosomes in the GnomAD database, including 1,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E377E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.035 ( 208 hom., cov: 33)

Exomes 𝑓: 0.018 ( 967 hom. )

Consequence

SMARCAL1
NM_014140.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 5.67

Publications

22 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 -16 ACMG points.

BP6

Variant 2-216423665-G-C is Benign according to our data. Variant chr2-216423665-G-C is described in ClinVar as Benign. ClinVar VariationId is 198202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCAL1	NM_014140.4 link	c.1129G>C	p.Glu377Gln	missense_variant	Exon 6 of 18	ENST00000357276.9	NP_054859.2
SMARCAL1	NM_001127207.2 link	c.1129G>C	p.Glu377Gln	missense_variant	Exon 6 of 18		NP_001120679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCAL1	ENST00000357276.9 link	c.1129G>C	p.Glu377Gln	missense_variant	Exon 6 of 18	2	NM_014140.4	ENSP00000349823.4

Frequencies

GnomAD3 genomes

AF:

0.0351

AC:

5346

AN:

152152

Hom.:

210

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0745

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0130

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.158

Gnomad SAS

AF:

0.0684

Gnomad FIN

AF:

0.00829

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.00964

Gnomad OTH

AF:

0.0335

GnomAD2 exomes

AF:

0.0323

AC:

8121

AN:

251456

AF XY:

0.0324

show subpopulations

Gnomad AFR exome

AF:

0.0738

Gnomad AMR exome

AF:

0.00942

Gnomad ASJ exome

AF:

0.0230

Gnomad EAS exome

AF:

0.157

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.0236

GnomAD4 exome

AF:

0.0182

AC:

26634

AN:

1461474

Hom.:

967

Cov.:

AF XY:

0.0194

AC XY:

14134

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.0753

AC:

2518

AN:

33456

American (AMR)

AF:

0.00982

AC:

439

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0229

AC:

599

AN:

26130

East Asian (EAS)

AF:

0.161

AC:

6404

AN:

39696

South Asian (SAS)

AF:

0.0637

AC:

5496

AN:

86232

European-Finnish (FIN)

AF:

0.0102

AC:

544

AN:

53378

Middle Eastern (MID)

AF:

0.0560

AC:

323

AN:

5764

European-Non Finnish (NFE)

AF:

0.00781

AC:

8677

AN:

1111716

Other (OTH)

AF:

0.0271

AC:

1634

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1358

2716

4074

5432

6790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

482

964

1446

1928

2410

<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:

0.0351

AC:

5341

AN:

152270

Hom.:

208

Cov.:

AF XY:

0.0365

AC XY:

2721

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0744

AC:

3091

AN:

41544

American (AMR)

AF:

0.0129

AC:

197

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

AN:

3466

East Asian (EAS)

AF:

0.158

AC:

821

AN:

5182

South Asian (SAS)

AF:

0.0678

AC:

327

AN:

4824

European-Finnish (FIN)

AF:

0.00829

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00966

AC:

657

AN:

68020

Other (OTH)

AF:

0.0331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

248

496

745

993

1241

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:

0.0175

Hom.:

Bravo

AF:

0.0371

TwinsUK

AF:

0.00701

AC:

ESP6500AA

AF:

0.0783

AC:

345

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.0333

AC:

4040

Asia WGS

AF:

0.104

AC:

362

AN:

3478

EpiCase

AF:

0.0110

EpiControl

AF:

0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Schimke immuno-osseous dysplasia

Benign:5

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

Nov 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 06, 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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:4

Oct 21, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27884173, 17089404, 25748404, 20981092)

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Focal segmental glomerulosclerosis

Benign:1

Sep 27, 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

0.15

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

T;T;T;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.46

LIST_S2

Benign

0.0

.;D;D;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Uncertain

2.6

M;M;.;.

PhyloP100

5.7

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.1

N;N;N;N

Sift

Benign

0.068

T;T;T;D

Sift4G

Uncertain

0.041

D;D;T;D

Vest4

0.083

ClinPred

0.025

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.42

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.31

Position offset: 18

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