chr2-216450927-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_014140.4(SMARCAL1):​c.1933C>T​(p.Arg645Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SMARCAL1
NM_014140.4 missense

Scores

18
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.09
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 2-216450927-C-T is Pathogenic according to our data. Variant chr2-216450927-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SMARCAL1NM_014140.4 linkc.1933C>T p.Arg645Cys missense_variant 12/18 ENST00000357276.9 NP_054859.2 Q9NZC9
SMARCAL1NM_001127207.2 linkc.1933C>T p.Arg645Cys missense_variant 12/18 NP_001120679.1 Q9NZC9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SMARCAL1ENST00000357276.9 linkc.1933C>T p.Arg645Cys missense_variant 12/182 NM_014140.4 ENSP00000349823.4 Q9NZC9

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152184
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251226
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135842
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461840
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.0000383
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:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152184
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Schimke immuno-osseous dysplasia Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 01, 2024- -
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 2002- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 05, 2023This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 645 of the SMARCAL1 protein (p.Arg645Cys). This variant is present in population databases (rs119473037, gnomAD 0.02%). This missense change has been observed in individuals with Schimke immuno-osseous dysplasia (PMID: 11799392, 22998683, 25748404). ClinVar contains an entry for this variant (Variation ID: 4175). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMARCAL1 protein function. Experimental studies have shown that this missense change affects SMARCAL1 function (PMID: 18805831). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.65
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.85
D;D;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
.;D;D
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
5.2
H;H;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-7.7
D;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.93
MutPred
0.97
Loss of MoRF binding (P = 0.0071);Loss of MoRF binding (P = 0.0071);.;
MVP
1.0
MPC
0.98
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.95
gMVP
0.88

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs119473037; hg19: chr2-217315650; COSMIC: COSV61921141; COSMIC: COSV61921141; API