Genetic Variant NM_014140.4:c.423T>C (chr2-216415127-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_014140.4(SMARCAL1):c.423T>C(p.Tyr141Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,613,408 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 9 hom., cov: 33)

Exomes 𝑓: 0.012 ( 138 hom. )

Consequence

SMARCAL1
NM_014140.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.0690

Publications

5 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 2-216415127-T-C is Benign according to our data. Variant chr2-216415127-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.069 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0092 (1402/152348) while in subpopulation AMR AF = 0.015 (230/15304). AF 95% confidence interval is 0.0134. There are 9 homozygotes in GnomAd4. There are 657 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 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.423T>C	p.Tyr141Tyr	synonymous	Exon 3 of 18	NP_054859.2
	SMARCAL1	NM_001127207.2		c.423T>C	p.Tyr141Tyr	synonymous	Exon 3 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.423T>C	p.Tyr141Tyr	synonymous	Exon 3 of 18	ENSP00000349823.4	Q9NZC9
SMARCAL1	ENST00000358207.9	TSL:1	c.423T>C	p.Tyr141Tyr	synonymous	Exon 3 of 18	ENSP00000350940.5	Q9NZC9
SMARCAL1	ENST00000392128.6	TSL:1	c.15T>C	p.Tyr5Tyr	synonymous	Exon 1 of 15	ENSP00000375974.2	H7BYI2

Frequencies

GnomAD3 genomes

AF:

0.00921

AC:

1402

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0150

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0101

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0132

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00969

AC:

2435

AN:

251164

AF XY:

0.0106

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.00773

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00366

Gnomad NFE exome

AF:

0.0136

Gnomad OTH exome

AF:

0.0131

GnomAD4 exome

AF:

0.0117

AC:

17086

AN:

1461060

Hom.:

138

Cov.:

AF XY:

0.0118

AC XY:

8593

AN XY:

726790

show subpopulations

African (AFR)

AF:

0.00198

AC:

AN:

33364

American (AMR)

AF:

0.00883

AC:

394

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

288

AN:

26118

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.0104

AC:

895

AN:

86240

European-Finnish (FIN)

AF:

0.00479

AC:

256

AN:

53414

Middle Eastern (MID)

AF:

0.0154

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0129

AC:

14389

AN:

1111508

Other (OTH)

AF:

0.0117

AC:

706

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1037

2075

3112

4150

5187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.00920

AC:

1402

AN:

152348

Hom.:

Cov.:

AF XY:

0.00882

AC XY:

657

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00255

AC:

106

AN:

41588

American (AMR)

AF:

0.0150

AC:

230

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0102

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00282

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0132

AC:

899

AN:

68030

Other (OTH)

AF:

0.0147

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

147

220

294

367

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:

0.0115

Hom.:

Bravo

AF:

0.00968

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0144

EpiControl

AF:

0.0149

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 (5)

not provided (3)

Focal segmental glomerulosclerosis (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.1

(source)

DANN

Benign

0.70

PhyloP100

-0.069

PromoterAI

0.038

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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