rs146084305

Positions:

• chr2-216420337-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014140.4(SMARCAL1):​c.901C>G​(p.Pro301Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00139 in 1,614,122 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (14 hom.)
• Consequence: SMARCAL1 NM_014140.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.34

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007854283).
• BP6: Variant 2-216420337-C-G is Benign according to our data. Variant chr2-216420337-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 260347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-216420337-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0074 (1127/152252) while in subpopulation AFR AF= 0.0255 (1058/41542). AF 95% confidence interval is 0.0242. There are 6 homozygotes in gnomad4. There are 523 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCAL1	NM_014140.4	c.901C>G	p.Pro301Ala	missense_variant	5/18	ENST00000357276.9
SMARCAL1	NM_001127207.2	c.901C>G	p.Pro301Ala	missense_variant	5/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCAL1	ENST00000357276.9	c.901C>G	p.Pro301Ala	missense_variant	5/18	2	NM_014140.4	P1

Frequencies

GnomAD3 genomes AF: 0.00739 AC: 1124 AN: 152134 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00194 AC: 487 AN: 251314 Hom.: 4 AF XY: 0.00155 AC XY: 211 AN XY: 135852

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000764 AC: 1117 AN: 1461870 Hom.: 14 Cov.: 32 AF XY: 0.000716 AC XY: 521 AN XY: 727236

Gnomad4 AFR exome AF: 0.0237

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00740 AC: 1127 AN: 152252 Hom.: 6 Cov.: 32 AF XY: 0.00703 AC XY: 523 AN XY: 74442

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00223 Hom.: 0

Bravo AF: 0.00839

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0243 AC: 107

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00238 AC: 289

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Schimke immuno-osseous dysplasia Benign:6

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jul 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jun 22, 2016	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T;T;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0079	T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.9	M;M;.;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D
REVEL	Benign	0.28
Sift	Benign	0.16	T;T;T;T;T
Sift4G	Benign	0.18	T;T;D;T;D
Polyphen		0.66	P;P;.;.;.
Vest4		0.45
MVP		0.80
MPC		0.71
ClinPred		0.033	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs146084305; hg19: chr2-217285060;