rs750671325

Positions:

• chr2-216415480-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014140.4(SMARCAL1):​c.776T>C​(p.Ile259Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I259I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SMARCAL1 NM_014140.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.50

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCAL1	NM_014140.4	c.776T>C	p.Ile259Thr	missense_variant	3/18	ENST00000357276.9
SMARCAL1	NM_001127207.2	c.776T>C	p.Ile259Thr	missense_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCAL1	ENST00000357276.9	c.776T>C	p.Ile259Thr	missense_variant	3/18	2	NM_014140.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249172 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134888

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461816 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727216

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000127 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Schimke immuno-osseous dysplasia Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 02, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 259 of the SMARCAL1 protein (p.Ile259Thr). This variant is present in population databases (rs750671325, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SMARCAL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 566403). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;T;T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.6	M;M;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.6	N;N;D;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.82	P;P;.;.
Vest4		0.29
MutPred		0.77		Loss of stability (P = 0.0361);Loss of stability (P = 0.0361);.;.;
MVP		0.90
MPC		0.79
ClinPred		0.58	D
GERP RS		5.2
Varity_R		0.24
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs750671325; hg19: chr2-217280203;