rs1554618664

Variant names:

• chr9-2056738-G-A
• rs1554618664
• NM_003070.5:c.1240G>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]

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 the SMARCA2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 88 curated benign missense variants. Gene score misZ: 5.054 (above the threshold of 3.09). Trascript score misZ: 4.663 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability-sparse hair-brachydactyly syndrome, Coffin-Siris syndrome 1.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.1240G>A	p.Ala414Thr	missense_variant	Exon 7 of 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

Oct 10, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 08, 2017

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing;provider interpretation

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;