Genetic Variant SMARCAL1:p.Ile548Asn (chr2-216435495-T-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_014140.4(SMARCAL1):c.1643T>A(p.Ile548Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I548V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SMARCAL1
NM_014140.4 missense, splice_region

Scores

Splicing: ADA: 0.6680

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.97

Publications

7 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 2-216435495-T-A is Pathogenic according to our data. Variant chr2-216435495-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4174.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1643T>A	p.Ile548Asn	missense splice_region	Exon 9 of 18	NP_054859.2
	SMARCAL1	NM_001127207.2		c.1643T>A	p.Ile548Asn	missense splice_region	Exon 9 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.1643T>A	p.Ile548Asn	missense splice_region	Exon 9 of 18	ENSP00000349823.4	Q9NZC9
SMARCAL1	ENST00000358207.9	TSL:1	c.1643T>A	p.Ile548Asn	missense splice_region	Exon 9 of 18	ENSP00000350940.5	Q9NZC9
SMARCAL1	ENST00000392128.6	TSL:1	c.1235T>A	p.Ile412Asn	missense splice_region	Exon 7 of 15	ENSP00000375974.2	H7BYI2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Schimke immuno-osseous dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

3.6

PhyloP100

8.0

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.97

MutPred

0.93

Loss of stability (P = 0.0343)

MVP

0.99

MPC

1.1

ClinPred

1.0

GERP RS

5.8

Varity_R

0.80

gMVP

0.87

Mutation Taster

=39/61

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.67

dbscSNV1_RF

Benign

0.52

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over