rs11555797

chr2-216415045-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014140.4(SMARCAL1):c.341G>A(p.Arg114His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,614,198 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R114C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0069 (42 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (191 hom.)
• Consequence: SMARCAL1 NM_014140.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0140

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018410981).
• BP6: Variant 2-216415045-G-A is Benign according to our data. Variant chr2-216415045-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-216415045-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCAL1	NM_014140.4	c.341G>A	p.Arg114His	missense_variant	3/18	ENST00000357276.9
SMARCAL1	NM_001127207.2	c.341G>A	p.Arg114His	missense_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCAL1	ENST00000357276.9	c.341G>A	p.Arg114His	missense_variant	3/18	2	NM_014140.4	P1

Frequencies

GnomAD3 genomes AF: 0.00689 AC: 1049 AN: 152204 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0611

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.0141 AC: 3538 AN: 251446 Hom.: 167 AF XY: 0.0107 AC XY: 1458 AN XY: 135898

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0144

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00864

GnomAD4 exome AF: 0.00322 AC: 4707 AN: 1461876 Hom.: 191 Cov.: 32 AF XY: 0.00276 AC XY: 2007 AN XY: 727242

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.0865

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0162

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00689 AC: 1049 AN: 152322 Hom.: 42 Cov.: 33 AF XY: 0.00815 AC XY: 607 AN XY: 74488

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.0609

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0123

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00206 Hom.: 10

Bravo AF: 0.0108

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0102 AC: 1233

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 28, 2015	- -

Schimke immuno-osseous dysplasia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	4.0
Dann	Benign	0.74
DEOGEN2	Benign	0.0034	T;T;.;T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.61	T;.;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.22	N;N;N;N;N
REVEL	Benign	0.042
Sift	Benign	0.15	T;T;T;T;T
Sift4G	Uncertain	0.035	D;T;D;T;D
Polyphen		0.73	.;P;.;P;.
Vest4		0.045, 0.043
MPC		0.28
ClinPred		0.011	T
GERP RS		3.8
Varity_R		0.022
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs11555797; hg19: chr2-217279768; COSMIC: COSV61922554; COSMIC: COSV61922554;