2-216412607-A-G

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.-137A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 152,610 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (96 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (0 hom.)
• Consequence: SMARCAL1 NM_014140.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.05

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=-0.85).
• BP6: Variant 2-216412607-A-G is Benign according to our data. Variant chr2-216412607-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 334285.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCAL1	NM_014140.4	c.-137A>G		5_prime_UTR_variant	1/18	ENST00000357276.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCAL1	ENST00000357276.9	c.-137A>G		5_prime_UTR_variant	1/18	2	NM_014140.4	P1
SMARCAL1-AS1	ENST00000457694.1	n.90T>C		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 3004 AN: 152200 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.0683

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00340 AC: 1 AN: 294 Hom.: 0 Cov.: 0 AF XY: 0.00442 AC XY: 1 AN XY: 226

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0198 AC: 3014 AN: 152316 Hom.: 96 Cov.: 32 AF XY: 0.0191 AC XY: 1421 AN XY: 74486

Gnomad4 AFR AF: 0.0684

Gnomad4 AMR AF: 0.00837

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0167 Hom.: 9

Bravo AF: 0.0222

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Schimke immuno-osseous dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	3.9
Dann	Benign	0.52

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: rs115172989; hg19: chr2-217277330;