rs35907255

chr2-216415127-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014140.4(SMARCAL1):c.423T>C(p.Tyr141=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,613,408 control chromosomes in the GnomAD database, including 147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (9 hom., cov: 33)
  • Exomes 𝑓: 0.012 (138 hom.)
• Consequence: SMARCAL1 NM_014140.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0690

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-216415127-T-C is Benign according to our data. Variant chr2-216415127-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 260344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.069 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0092 (1402/152348) while in subpopulation AMR AF= 0.015 (230/15304). AF 95% confidence interval is 0.0134. There are 9 homozygotes in gnomad4. There are 657 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCAL1	NM_014140.4	c.423T>C	p.Tyr141=	synonymous_variant	3/18	ENST00000357276.9
SMARCAL1	NM_001127207.2	c.423T>C	p.Tyr141=	synonymous_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCAL1	ENST00000357276.9	c.423T>C	p.Tyr141=	synonymous_variant	3/18	2	NM_014140.4	P1

Frequencies

GnomAD3 genomes AF: 0.00921 AC: 1402 AN: 152230 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00969 AC: 2435 AN: 251164 Hom.: 27 AF XY: 0.0106 AC XY: 1439 AN XY: 135748

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00773

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0105

Gnomad FIN exome AF: 0.00366

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0117 AC: 17086 AN: 1461060 Hom.: 138 Cov.: 32 AF XY: 0.0118 AC XY: 8593 AN XY: 726790

Gnomad4 AFR exome AF: 0.00198

Gnomad4 AMR exome AF: 0.00883

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.00479

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.00920 AC: 1402 AN: 152348 Hom.: 9 Cov.: 33 AF XY: 0.00882 AC XY: 657 AN XY: 74492

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.00282

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0108 Hom.: 2

Bravo AF: 0.00968

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0144

EpiControl AF: 0.0149

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Schimke immuno-osseous dysplasia Benign:5

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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SMARCAL1: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	1.1
Dann	Benign	0.70

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: rs35907255; hg19: chr2-217279850;