2-216412526-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014140.4(SMARCAL1):c.-218C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,270 control chromosomes in the GnomAD database, including 4,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4913 hom., cov: 33)
  • Exomes 𝑓: 0.24 (3 hom.)
• Consequence: SMARCAL1 NM_014140.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.512

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-AS1 (HGNC:40555): (SMARCAL1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-216412526-C-T is Benign according to our data. Variant chr2-216412526-C-T is described in ClinVar as [Benign]. Clinvar id is 334280.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-216412526-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCAL1	NM_014140.4	c.-218C>T		5_prime_UTR_variant	1/18	ENST00000357276.9
SMARCAL1-AS1	XR_001739881.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCAL1	ENST00000357276.9	c.-218C>T		5_prime_UTR_variant	1/18	2	NM_014140.4	P1
SMARCAL1-AS1	ENST00000457694.1	n.171G>A		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34784 AN: 152098 Hom.: 4914 Cov.: 33

Gnomad AFR AF: 0.0558

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.241 AC: 13 AN: 54 Hom.: 3 Cov.: 0 AF XY: 0.237 AC XY: 9 AN XY: 38

Gnomad4 AFR exome AF: 0.250

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.275

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.228 AC: 34769 AN: 152216 Hom.: 4913 Cov.: 33 AF XY: 0.230 AC XY: 17126 AN XY: 74428

Gnomad4 AFR AF: 0.0556

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.324

Gnomad4 EAS AF: 0.270

Gnomad4 SAS AF: 0.288

Gnomad4 FIN AF: 0.317

Gnomad4 NFE AF: 0.311

Gnomad4 OTH AF: 0.231

Alfa AF: 0.262 Hom.: 911

Bravo AF: 0.214

Asia WGS AF: 0.233 AC: 809 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Schimke immuno-osseous dysplasia Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	5.2
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs3755141; hg19: chr2-217277249;