9-2110275-G-A

Position:

• chr9-2110275-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_003070.5(SMARCA2):​c.3314G>A​(p.Arg1105His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1105C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain Helicase C-terminal (size 162) in uniprot entity SMCA2_HUMAN there are 25 pathogenic changes around while only 0 benign (100%) in NM_003070.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-2110274-C-T is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 9-2110275-G-A is Pathogenic according to our data. Variant chr9-2110275-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 982859.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3}. Variant chr9-2110275-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.3314G>A	p.Arg1105His	missense_variant	24/34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.1	c.3314G>A	p.Arg1105His	missense_variant	24/34		NP_001276325.1
SMARCA2	NM_139045.4	c.3314G>A	p.Arg1105His	missense_variant	24/33		NP_620614.2
SMARCA2	NM_001289397.2	c.3140G>A	p.Arg1047His	missense_variant	24/33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.3314G>A	p.Arg1105His	missense_variant	24/34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nicolaides-Baraitser syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 02, 2020	This variant was identified as de novo (maternity and paternity confirmed). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2024

The p.R1105H pathogenic mutation (also known as c.3314G>A) is located in exon 24 (coding exon 23) of the SMARCA2 gene. This alteration results from a G to A substitution at nucleotide position 3314, causing the arginine (R) at amino acid position 1105 to be replaced by a histidine (H). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with SMARCA2-related neurodevelopmental disorder; in at least one instance, this variant has been determined to be the result of a de novo mutation (Santen, 2013; Vissers, 2017; Henriquez-Lopez, 2023; Ambry internal data). Other alterations at the same codon, c.3313C>T (p.R1105C) and c.3314G>C (p.R1105P), have been reported in individuals with features consistent with SMARCA2-related neurodevelopmental disorder (Van Houdt, 2012). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis and located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Blepharophimosis-impaired intellectual development syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;.;D;.;D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;.;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.5	H;.;H;H;H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.7	D;.;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;D;D;D
Vest4		0.93
MutPred		0.86		Gain of ubiquitination at K1110 (P = 0.0499);.;Gain of ubiquitination at K1110 (P = 0.0499);Gain of ubiquitination at K1110 (P = 0.0499);Gain of ubiquitination at K1110 (P = 0.0499);
MVP		0.96
MPC		2.6
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs281875197; hg19: chr9-2110275; COSMIC: COSV61806697; COSMIC: COSV61806697;