NM_014140.4:c.2528+5G>C

Variant names:

• chr2-216477214-G-C
• rs145908212
• NM_014140.4:c.2528+5G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS1

The NM_014140.4(SMARCAL1):​c.2528+5G>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000242 in 1,575,828 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: SMARCAL1 NM_014140.4 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 4.29
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Schimke immuno-osseous dysplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-216477214-G-C is Benign according to our data. Variant chr2-216477214-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287872.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00123 (188/152308) while in subpopulation AFR AF = 0.00438 (182/41562). AF 95% confidence interval is 0.00386. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014140.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCAL1	NM_014140.4	MANE Select	c.2528+5G>C		splice_region intron	N/A	NP_054859.2
	SMARCAL1	NM_001127207.2		c.2528+5G>C		splice_region intron	N/A	NP_001120679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCAL1	ENST00000357276.9	TSL:2 MANE Select	c.2528+5G>C		splice_region intron	N/A	ENSP00000349823.4
	SMARCAL1	ENST00000358207.9	TSL:1	c.2528+5G>C		splice_region intron	N/A	ENSP00000350940.5
	SMARCAL1	ENST00000392128.6	TSL:1	c.2054+5G>C		splice_region intron	N/A	ENSP00000375974.2

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000289 AC: 56 AN: 193870 AF XY: 0.000194

Gnomad AFR exome AF: 0.00427

Gnomad AMR exome AF: 0.000215

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.000136 AC: 194 AN: 1423520 Hom.: 1 Cov.: 29 AF XY: 0.000116 AC XY: 82 AN XY: 704862

African (AFR) AF: 0.00491 AC: 161 AN: 32790

American (AMR) AF: 0.000230 AC: 9 AN: 39212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25456

East Asian (EAS) AF: 0.00 AC: 0 AN: 38280

South Asian (SAS) AF: 0.0000246 AC: 2 AN: 81272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51136

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5620

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090692

Other (OTH) AF: 0.000322 AC: 19 AN: 59062

GnomAD4 genome AF: 0.00123 AC: 188 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.00124 AC XY: 92 AN XY: 74484

African (AFR) AF: 0.00438 AC: 182 AN: 41562

American (AMR) AF: 0.000262 AC: 4 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000448 Hom.: 0

Bravo AF: 0.00151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Schimke immuno-osseous dysplasia Uncertain:1 Benign:1

Jan 24, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Apr 03, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Focal segmental glomerulosclerosis Uncertain:1

Jun 04, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMARCAL1-related disorder Benign:1

Sep 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	16
DANN	Benign	0.69
PhyloP100		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145908212; hg19: chr2-217341937;