rs1554618664

Positions:

• chr9-2056738-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003070.5(SMARCA2):​c.1240G>A​(p.Ala414Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.97

Genes affected

SMARCA2 (HGNC:11098): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is highly similar to the brahma protein of Drosophila. 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 is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. Alternatively spliced transcript variants encoding different isoforms have been found for this gene, which contains a trinucleotide repeat (CAG) length polymorphism. [provided by RefSeq, Jan 2014]

SMARCA2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA2. . Gene score misZ 5.054 (greater than the threshold 3.09). Trascript score misZ 4.663 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability-sparse hair-brachydactyly syndrome, Coffin-Siris syndrome 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.1240G>A	p.Ala414Thr	missense_variant	7/34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.1	c.1240G>A	p.Ala414Thr	missense_variant	7/34		NP_001276325.1
SMARCA2	NM_139045.4	c.1240G>A	p.Ala414Thr	missense_variant	7/33		NP_620614.2
SMARCA2	NM_001289397.2	c.1240G>A	p.Ala414Thr	missense_variant	7/33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.1240G>A	p.Ala414Thr	missense_variant	7/34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 10, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25724810, 22426309, 22426308, 22366787) -

Nicolaides-Baraitser syndrome;C3281201:Coffin-Siris syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Nov 08, 2017

This 5 year old female with mild global developmental delays, cerebral ventriculomegaly, and hypotonia carries a missense variant in the gene SMARCA2. Inheritance is currently unknown as her father is unavailable to provide a sample; he is reported to have an intellectual disability but no physical abnormalities. Clinical correlation is felt to be poor, as she does not have the majority of the common features of Coffin-Siris or Nicolaides-Baraitser syndromes. Of note, she has hypoplastic nails on her fifth toes, which is seen in Coffin-Siris syndrome. The p.Ala414Thr variant is absent from population databases and has not been reported previously in affected individuals, to our knowledge. Computational models predict the variant to be probably damaging. The variant is currently considered to be of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.069	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	.;.;D;.;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;.;D;D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.62	D;D;D;D;D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.7	M;.;M;M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.3	D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.044	D;D;D;D;D
Sift4G	Benign	0.092	T;T;T;T;T
Polyphen		1.0	D;.;D;D;D
Vest4		0.71
MutPred		0.31		Gain of phosphorylation at A414 (P = 0.0205);Gain of phosphorylation at A414 (P = 0.0205);Gain of phosphorylation at A414 (P = 0.0205);Gain of phosphorylation at A414 (P = 0.0205);Gain of phosphorylation at A414 (P = 0.0205);
MVP		0.66
MPC		1.9
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.41
gMVP		0.93

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

Other links and lift over

dbSNP: rs1554618664; hg19: chr9-2056738;