Variant 2-216414709-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_014140.4(SMARCAL1):c.5C>T(p.Ser2Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,548 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SMARCAL1
NM_014140.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.50

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a modified_residue N-acetylserine (size 0) in uniprot entity SMAL1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCAL1	NM_014140.4 linkuse as main transcript	c.5C>T	p.Ser2Phe	missense_variant	3/18	ENST00000357276.9
SMARCAL1	NM_001127207.2 linkuse as main transcript	c.5C>T	p.Ser2Phe	missense_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCAL1	ENST00000357276.9 linkuse as main transcript	c.5C>T	p.Ser2Phe	missense_variant	3/18	2	NM_014140.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250274

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461548

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Schimke immuno-osseous dysplasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2021

This sequence change replaces serine with phenylalanine at codon 2 of the SMARCAL1 protein (p.Ser2Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs771595818, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with SMARCAL1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T;.;T;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;.;T;.;T;T

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.63

D;D;D;D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.6

.;M;.;.;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-5.7

D;N;D;D;N;D

REVEL

Benign

0.23

Sift

Pathogenic

0.0

D;D;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;.;D;D

Polyphen

1.0

.;D;.;.;D;.

Vest4

0.51

MutPred

0.24

Loss of phosphorylation at S2 (P = 0.0108);Loss of phosphorylation at S2 (P = 0.0108);Loss of phosphorylation at S2 (P = 0.0108);Loss of phosphorylation at S2 (P = 0.0108);Loss of phosphorylation at S2 (P = 0.0108);Loss of phosphorylation at S2 (P = 0.0108);

MVP

0.96

MPC

0.87

ClinPred

0.99

GERP RS

5.2

Varity_R

0.34

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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