NM_003070.5:c.3485G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_003070.5(SMARCA2):c.3485G>A(p.Arg1162His) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMARCA2
NM_003070.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 10.0

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 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

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 9-2115850-G-A is Pathogenic according to our data. Variant chr9-2115850-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2115850-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5 link	c.3485G>A	p.Arg1162His	missense_variant	Exon 25 of 34	ENST00000349721.8	NP_003061.3	P51531-1Q8N9Q1Q56A76
SMARCA2	NM_001289396.2 link	c.3485G>A	p.Arg1162His	missense_variant	Exon 25 of 34		NP_001276325.1	P51531-1Q8N9Q1B4DSC8
SMARCA2	NM_139045.4 link	c.3485G>A	p.Arg1162His	missense_variant	Exon 25 of 33		NP_620614.2	P51531-2Q8N9Q1Q56A76
SMARCA2	NM_001289397.2 link	c.3311G>A	p.Arg1104His	missense_variant	Exon 25 of 33		NP_001276326.1	P51531F6VDE0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8 link	c.3485G>A	p.Arg1162His	missense_variant	Exon 25 of 34	5	NM_003070.5	ENSP00000265773.5		P51531-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461684

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727144

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.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Nicolaides-Baraitser syndrome

Pathogenic:3

Jun 09, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 26, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 01, 2018

CeGaT Center for Human Genetics Tuebingen

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

0.59

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

.;.;D;.;D

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

.;D;.;D;D

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

5.2

H;.;H;H;H

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-4.6

D;.;D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.97

D;.;D;D;D

Vest4

0.94

MutPred

0.94

Loss of MoRF binding (P = 0.039);.;Loss of MoRF binding (P = 0.039);Loss of MoRF binding (P = 0.039);Loss of MoRF binding (P = 0.039);

MVP

0.99

MPC

2.6

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over