NM_003070.5:c.3313C>T

Variant names:

• chr9-2110274-C-T
• rs281875192
• NM_003070.5:c.3313C>T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_003070.5(SMARCA2):​c.3313C>T​(p.Arg1105Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 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. R1105H) 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:3 O:1
• Conservation: PhyloP100: 4.97

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 Pathogenic. Variant got 19 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 chr9-2110275-G-A is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 9-2110274-C-T is Pathogenic according to our data. Variant chr9-2110274-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 68769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2110274-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.3313C>T	p.Arg1105Cys	missense_variant	Exon 24 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2	c.3313C>T	p.Arg1105Cys	missense_variant	Exon 24 of 34		NP_001276325.1
SMARCA2	NM_139045.4	c.3313C>T	p.Arg1105Cys	missense_variant	Exon 24 of 33		NP_620614.2
SMARCA2	NM_001289397.2	c.3139C>T	p.Arg1047Cys	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.3313C>T	p.Arg1105Cys	missense_variant	Exon 24 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SMARCA2: PS2, PM1, PM2, PS4:Moderate, PP2, PP3, PP4 -

Oct 31, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25249037, 22366787, 35811451) -

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nicolaides-Baraitser syndrome Pathogenic:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the helicase conserved C-terminal domain (DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Four alternative amino acid changes have been observed at this position in at least nine unrelated individuals with SMARCA2-related conditions (Clinvar, LOVD, PMIDs: 28333917, 23929686, 22366787). (SP) 0803 - This variant has limited previous evidence of pathogenicity in two unrelated individuals. This variant has been observed in two individuals with SMARCA2-related conditions, including one de novo case (ClinVar, LOVD, PMID: 28333917). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	.;.;D;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	.;D;.;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.1	H;.;H;H;H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.4	D;.;D;D;D
REVEL	Pathogenic	0.87
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		0.97
MutPred		0.87		Loss of disorder (P = 0.0188);.;Loss of disorder (P = 0.0188);Loss of disorder (P = 0.0188);Loss of disorder (P = 0.0188);
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
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: rs281875192; hg19: chr9-2110274; COSMIC: COSV61805239; COSMIC: COSV61805239;