NM_003070.5:c.3314G>A

Variant names:

• chr9-2110275-G-A
• rs281875197
• NM_003070.5:c.3314G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1105P) has been classified as Likely 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
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability-sparse hair-brachydactyly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a domain Helicase C-terminal (size 162) in uniprot entity SMCA2_HUMAN there are 41 pathogenic changes around while only 6 benign (87%) 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 chr9-2110275-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 [Pathogenic]. Clinvar id is 982859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.3314G>A	p.Arg1105His	missense_variant	Exon 24 of 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

Jul 01, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 02, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed). -

Inborn genetic diseases Pathogenic:1

Aug 13, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 01, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		10
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
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		1.0
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs281875197; hg19: chr9-2110275; COSMIC: COSV61806697; COSMIC: COSV61806697;