rs58848916

Variant names:

• chr2-216428691-A-G
• rs58848916
• NM_014140.4:c.1243A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014140.4(SMARCAL1):​c.1243A>G​(p.Ser415Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,138 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S415S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (14 hom.)
• Consequence: SMARCAL1 NM_014140.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.224
• 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: ClinGen, PanelApp Australia, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032710433).
• BP6: Variant 2-216428691-A-G is Benign according to our data. Variant chr2-216428691-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 463145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0072 (1097/152296) while in subpopulation AFR AF = 0.025 (1040/41560). AF 95% confidence interval is 0.0238. There are 11 homozygotes in GnomAd4. There are 511 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCAL1	NM_014140.4	MANE Select	c.1243A>G	p.Ser415Gly	missense	Exon 7 of 18	NP_054859.2
	SMARCAL1	NM_001127207.2		c.1243A>G	p.Ser415Gly	missense	Exon 7 of 18	NP_001120679.1	Q9NZC9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCAL1	ENST00000357276.9	TSL:2 MANE Select	c.1243A>G	p.Ser415Gly	missense	Exon 7 of 18	ENSP00000349823.4	Q9NZC9
	SMARCAL1	ENST00000358207.9	TSL:1	c.1243A>G	p.Ser415Gly	missense	Exon 7 of 18	ENSP00000350940.5	Q9NZC9
	SMARCAL1	ENST00000392128.6	TSL:1	c.835A>G	p.Ser279Gly	missense	Exon 5 of 15	ENSP00000375974.2	H7BYI2

Frequencies

GnomAD3 genomes AF: 0.00720 AC: 1095 AN: 152178 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00195 AC: 491 AN: 251490 AF XY: 0.00132

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000735 AC: 1074 AN: 1461842 Hom.: 14 Cov.: 32 AF XY: 0.000626 AC XY: 455 AN XY: 727228

African (AFR) AF: 0.0260 AC: 869 AN: 33478

American (AMR) AF: 0.00134 AC: 60 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111962

Other (OTH) AF: 0.00180 AC: 109 AN: 60396

GnomAD4 genome AF: 0.00720 AC: 1097 AN: 152296 Hom.: 11 Cov.: 33 AF XY: 0.00686 AC XY: 511 AN XY: 74472

African (AFR) AF: 0.0250 AC: 1040 AN: 41560

American (AMR) AF: 0.00281 AC: 43 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00762 Hom.: 4

Bravo AF: 0.00813

ESP6500AA AF: 0.0270 AC: 119

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00221 AC: 268

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Schimke immuno-osseous dysplasia (2)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.013
DANN	Benign	0.87
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.22
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.12
Sift	Benign	0.14	T
Sift4G	Benign	0.26	T
Polyphen		0.019	B
Vest4		0.029
MVP		0.67
MPC		0.20
ClinPred		0.0051	T
GERP RS		-1.1
PromoterAI		0.017	Neutral
Varity_R		0.033
gMVP		0.14
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs58848916; hg19: chr2-217293414;