9-2115967-C-T

Variant names:

• chr9-2115967-C-T
• rs281875189
• NM_003070.5:c.3602C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_003070.5(SMARCA2):​c.3602C>T​(p.Ala1201Val) 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. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.91

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 14 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
• 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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-2115967-C-T is Pathogenic according to our data. Variant chr9-2115967-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2115967-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.3602C>T	p.Ala1201Val	missense_variant	Exon 25 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2	c.3602C>T	p.Ala1201Val	missense_variant	Exon 25 of 34		NP_001276325.1
SMARCA2	NM_139045.4	c.3602C>T	p.Ala1201Val	missense_variant	Exon 25 of 33		NP_620614.2
SMARCA2	NM_001289397.2	c.3428C>T	p.Ala1143Val	missense_variant	Exon 25 of 33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.3602C>T	p.Ala1201Val	missense_variant	Exon 25 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 12, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this variant has a deleterious effect on splicing; 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: 22366787, 25169058, 24090879, 30459321) -

Hirsutism;C3714756:Intellectual disability Pathogenic:1

Sep 26, 2019

Autoinflammatory diseases unit, CHU de Montpellier

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nicolaides-Baraitser syndrome Pathogenic:1

Feb 26, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Intellectual disability Pathogenic:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

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	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;.;D;.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;.;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.8	M;.;M;M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.6	D;.;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;.;D;D;D
Vest4		0.87
MutPred		0.41		Loss of catalytic residue at A1201 (P = 0.0697);.;Loss of catalytic residue at A1201 (P = 0.0697);Loss of catalytic residue at A1201 (P = 0.0697);Loss of catalytic residue at A1201 (P = 0.0697);
MVP		0.98
MPC		2.0
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.71
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.74		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs281875189; hg19: chr9-2115967;