chr2-216414831-G-A

Position:

chr2-216414831-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014140.4(SMARCAL1):c.127G>A(p.Ala43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,614,194 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 47 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 32 hom. )

Consequence

SMARCAL1
NM_014140.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.407

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022759438).

BP6

Variant 2-216414831-G-A is Benign according to our data. Variant chr2-216414831-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-216414831-G-A is described in Lovd as [Likely_benign]. Variant chr2-216414831-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (2029/152300) while in subpopulation AFR AF= 0.0465 (1934/41554). AF 95% confidence interval is 0.0448. There are 47 homozygotes in gnomad4. There are 969 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCAL1	NM_014140.4 linkuse as main transcript	c.127G>A	p.Ala43Thr	missense_variant	3/18	ENST00000357276.9	NP_054859.2
SMARCAL1	NM_001127207.2 linkuse as main transcript	c.127G>A	p.Ala43Thr	missense_variant	3/18		NP_001120679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCAL1	ENST00000357276.9 linkuse as main transcript	c.127G>A	p.Ala43Thr	missense_variant	3/18	2	NM_014140.4	ENSP00000349823	P1

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2030

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0467

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00907

GnomAD3 exomes

AF:

0.00335

AC:

842

AN:

251470

Hom.:

AF XY:

0.00235

AC XY:

319

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0448

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00134

AC:

1957

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

813

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0458

Gnomad4 AMR exome

AF:

0.00250

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.00273

GnomAD4 genome

AF:

0.0133

AC:

2029

AN:

152300

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

969

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0465

Gnomad4 AMR

AF:

0.00373

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00898

Alfa

AF:

0.00279

Hom.:

Bravo

AF:

0.0152

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0474

AC:

209

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00402

AC:

488

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Schimke immuno-osseous dysplasia

Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2024	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

3.8

DANN

Benign

0.93

DEOGEN2

Benign

0.013

T;T;.;T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.55

T;.;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;L;.;L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.70

N;N;N;N;N

REVEL

Benign

0.010

Sift

Benign

0.19

T;T;T;T;T

Sift4G

Pathogenic

0.0

D;T;D;T;D

Polyphen

0.0020

.;B;.;B;.

Vest4

0.052, 0.053

MVP

0.24

MPC

0.22

ClinPred

0.0026

GERP RS

0.32

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.028

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over