rs119473036

Variant names:

• chr2-216435495-T-A
• rs119473036
• NM_014140.4:c.1643T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-216435495-T-A
• chr2-216435495-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

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

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)

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCAL1	NM_014140.4	c.1643T>A	p.Ile548Asn	missense_variant, splice_region_variant	Exon 9 of 18	ENST00000357276.9	NP_054859.2
SMARCAL1	NM_001127207.2	c.1643T>A	p.Ile548Asn	missense_variant, splice_region_variant	Exon 9 of 18		NP_001120679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCAL1	ENST00000357276.9	c.1643T>A	p.Ile548Asn	missense_variant, splice_region_variant	Exon 9 of 18	2	NM_014140.4	ENSP00000349823.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Schimke immuno-osseous dysplasia Pathogenic:1

Feb 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;D;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.6	H;H;.
PhyloP100		8.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.5	D;D;N
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0080	D;D;T
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.93		Loss of stability (P = 0.0343);Loss of stability (P = 0.0343);.;
MVP		0.99
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.80
gMVP		0.87
Mutation Taster		=39/61	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs119473036; hg19: chr2-217300218;