rs2066527

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014140.4(SMARCAL1):c.2070T>C(p.Thr690Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,612,622 control chromosomes in the GnomAD database, including 12,913 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.096 ( 878 hom., cov: 32)

Exomes 𝑓: 0.12 ( 12035 hom. )

Consequence

SMARCAL1
NM_014140.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0003744

Clinical Significance

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

Conservation

PhyloP100: -0.289

Publications

14 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 2-216451064-T-C is Benign according to our data. Variant chr2-216451064-T-C is described in ClinVar as Benign. ClinVar VariationId is 260341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.289 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCAL1	NM_014140.4 link	c.2070T>C	p.Thr690Thr	splice_region_variant, synonymous_variant	Exon 12 of 18	ENST00000357276.9	NP_054859.2	Q9NZC9
SMARCAL1	NM_001127207.2 link	c.2070T>C	p.Thr690Thr	splice_region_variant, synonymous_variant	Exon 12 of 18		NP_001120679.1	Q9NZC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCAL1	ENST00000357276.9 link	c.2070T>C	p.Thr690Thr	splice_region_variant, synonymous_variant	Exon 12 of 18	2	NM_014140.4	ENSP00000349823.4		Q9NZC9

Frequencies

GnomAD3 genomes

AF:

0.0965

AC:

14671

AN:

152098

Hom.:

875

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0482

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.0549

Gnomad ASJ

AF:

0.0830

Gnomad EAS

AF:

0.00828

Gnomad SAS

AF:

0.187

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.127

Gnomad OTH

AF:

0.0838

GnomAD2 exomes

AF:

0.109

AC:

27225

AN:

249660

AF XY:

0.117

show subpopulations

Gnomad AFR exome

AF:

0.0458

Gnomad AMR exome

AF:

0.0440

Gnomad ASJ exome

AF:

0.0797

Gnomad EAS exome

AF:

0.00648

Gnomad FIN exome

AF:

0.155

Gnomad NFE exome

AF:

0.125

Gnomad OTH exome

AF:

0.0971

GnomAD4 exome

AF:

0.122

AC:

178521

AN:

1460406

Hom.:

12035

Cov.:

AF XY:

0.125

AC XY:

90644

AN XY:

726630

show subpopulations

African (AFR)

AF:

0.0487

AC:

1628

AN:

33438

American (AMR)

AF:

0.0463

AC:

2070

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0773

AC:

2020

AN:

26132

East Asian (EAS)

AF:

0.00458

AC:

182

AN:

39698

South Asian (SAS)

AF:

0.193

AC:

16598

AN:

86206

European-Finnish (FIN)

AF:

0.152

AC:

8105

AN:

53340

Middle Eastern (MID)

AF:

0.0976

AC:

563

AN:

5766

European-Non Finnish (NFE)

AF:

0.127

AC:

140652

AN:

1110766

Other (OTH)

AF:

0.111

AC:

6703

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

7918

15836

23755

31673

39591

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5018

10036

15054

20072

25090

<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:

0.0965

AC:

14683

AN:

152216

Hom.:

878

Cov.:

AF XY:

0.0974

AC XY:

7250

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0486

AC:

2017

AN:

41542

American (AMR)

AF:

0.0548

AC:

838

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0830

AC:

288

AN:

3470

East Asian (EAS)

AF:

0.00830

AC:

AN:

5180

South Asian (SAS)

AF:

0.186

AC:

899

AN:

4826

European-Finnish (FIN)

AF:

0.156

AC:

1653

AN:

10576

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.127

AC:

8611

AN:

68012

Other (OTH)

AF:

0.0825

AC:

174

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

663

1326

1989

2652

3315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<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:

0.112

Hom.:

4473

Bravo

AF:

0.0836

Asia WGS

AF:

0.102

AC:

353

AN:

3478

EpiCase

AF:

0.121

EpiControl

AF:

0.115

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

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.8

(source)

DANN

Benign

0.73

PhyloP100

-0.29

Mutation Taster

=79/21

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00037

dbscSNV1_RF

Benign

0.084

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