rs146084305

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014140.4(SMARCAL1):c.901C>G(p.Pro301Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00139 in 1,614,122 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 14 hom. )

Consequence

SMARCAL1
NM_014140.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.34

Publications

2 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: ClinGen, PanelApp Australia, Orphanet, G2P, 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=0.007854283).

BP6

Variant 2-216420337-C-G is Benign according to our data. Variant chr2-216420337-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0074 (1127/152252) while in subpopulation AFR AF = 0.0255 (1058/41542). AF 95% confidence interval is 0.0242. There are 6 homozygotes in GnomAd4. There are 523 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014140.4. 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
	SMARCAL1	NM_014140.4	MANE Select	c.901C>G	p.Pro301Ala	missense	Exon 5 of 18	NP_054859.2
	SMARCAL1	NM_001127207.2		c.901C>G	p.Pro301Ala	missense	Exon 5 of 18	NP_001120679.1	Q9NZC9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMARCAL1	ENST00000357276.9	TSL:2 MANE Select	c.901C>G	p.Pro301Ala	missense	Exon 5 of 18	ENSP00000349823.4	Q9NZC9
SMARCAL1	ENST00000358207.9	TSL:1	c.901C>G	p.Pro301Ala	missense	Exon 5 of 18	ENSP00000350940.5	Q9NZC9
SMARCAL1	ENST00000392128.6	TSL:1	c.493C>G	p.Pro165Ala	missense	Exon 3 of 15	ENSP00000375974.2	H7BYI2

Frequencies

GnomAD3 genomes

AF:

0.00739

AC:

1124

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0255

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00194

AC:

487

AN:

251314

AF XY:

0.00155

show subpopulations

Gnomad AFR exome

AF:

0.0258

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000764

AC:

1117

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000716

AC XY:

521

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0237

AC:

794

AN:

33476

American (AMR)

AF:

0.00116

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000138

AC:

153

AN:

1112002

Other (OTH)

AF:

0.00174

AC:

105

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

122

184

245

306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00740

AC:

1127

AN:

152252

Hom.:

Cov.:

AF XY:

0.00703

AC XY:

523

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0255

AC:

1058

AN:

41542

American (AMR)

AF:

0.00288

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68016

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00223

Hom.:

Bravo

AF:

0.00839

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0243

AC:

107

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00238

AC:

289

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Schimke immuno-osseous dysplasia (6)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0079

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.9

PhyloP100

5.3

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.28

Sift

Benign

0.16

Sift4G

Benign

0.18

Polyphen

0.66

Vest4

0.45

MVP

0.80

MPC

0.71

ClinPred

0.033

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.55

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over