rs2066520

Variant names:

• chr2-216428719-A-T
• rs2066520
• NM_014140.4:c.1271A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014140.4(SMARCAL1):​c.1271A>T​(p.Asp424Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,614,204 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D424D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (12 hom.)
• Consequence: SMARCAL1 NM_014140.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 9.18
• Publications: 10 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014533311).
• BP6: Variant 2-216428719-A-T is Benign according to our data. Variant chr2-216428719-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283080.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00212 (323/152334) while in subpopulation NFE AF = 0.00353 (240/68028). AF 95% confidence interval is 0.00316. There are 0 homozygotes in GnomAd4. There are 144 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.1271A>T	p.Asp424Val	missense	Exon 7 of 18	NP_054859.2
	SMARCAL1	NM_001127207.2		c.1271A>T	p.Asp424Val	missense	Exon 7 of 18	NP_001120679.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCAL1	ENST00000357276.9	TSL:2 MANE Select	c.1271A>T	p.Asp424Val	missense	Exon 7 of 18	ENSP00000349823.4
	SMARCAL1	ENST00000358207.9	TSL:1	c.1271A>T	p.Asp424Val	missense	Exon 7 of 18	ENSP00000350940.5
	SMARCAL1	ENST00000392128.6	TSL:1	c.863A>T	p.Asp288Val	missense	Exon 5 of 15	ENSP00000375974.2

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 323 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00353

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00229 AC: 577 AN: 251494 AF XY: 0.00232

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00351

Gnomad OTH exome AF: 0.00423

GnomAD4 exome AF: 0.00310 AC: 4536 AN: 1461870 Hom.: 12 Cov.: 32 AF XY: 0.00311 AC XY: 2260 AN XY: 727234

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00121 AC: 54 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 79 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00145 AC: 125 AN: 86258

European-Finnish (FIN) AF: 0.00116 AC: 62 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00363 AC: 4037 AN: 1111988

Other (OTH) AF: 0.00270 AC: 163 AN: 60396

GnomAD4 genome AF: 0.00212 AC: 323 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.00193 AC XY: 144 AN XY: 74504

African (AFR) AF: 0.000505 AC: 21 AN: 41582

American (AMR) AF: 0.00176 AC: 27 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00353 AC: 240 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00322 Hom.: 0

Bravo AF: 0.00238

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00232 AC: 282

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00385

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	3	Schimke immuno-osseous dysplasia (4)
-	1	-	Kidney disorder (1)
-	-	1	not specified (1)
-	-	1	SMARCAL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.040	B
Vest4		0.67
MVP		0.97
MPC		0.98
ClinPred		0.077	T
GERP RS		6.1
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.79
Mutation Taster		=94/6	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: rs2066520; hg19: chr2-217293442; COSMIC: COSV99050872; COSMIC: COSV99050872;