19-11025467-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001387283.1(SMARCA4):c.3127C>T(p.Arg1043Trp) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1043R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

SMARCA4
NM_001387283.1 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: -0.449

Publications

10 publications found

Variant links:

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is 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. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 Gene-Disease associations (from GenCC):

Coffin-Siris syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
intellectual disability, autosomal dominant 16
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
rhabdoid tumor predisposition syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
uterine corpus sarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
familial rhabdoid tumor
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

SMARCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

PP5

Variant 19-11025467-C-T is Pathogenic according to our data. Variant chr19-11025467-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 436813.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
SMARCA4	NM_001387283.1 link	c.3127C>T	p.Arg1043Trp	missense_variant	Exon 22 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5 link	c.3127C>T	p.Arg1043Trp	missense_variant	Exon 22 of 35	ENST00000344626.10	NP_003063.2	P51532-1A7E2E1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMARCA4	ENST00000646693.2 link	c.3127C>T	p.Arg1043Trp	missense_variant	Exon 22 of 36		NM_001387283.1	ENSP00000495368.1	Q9HBD4
SMARCA4	ENST00000344626.10 link	c.3127C>T	p.Arg1043Trp	missense_variant	Exon 22 of 35	1	NM_003072.5	ENSP00000343896.4	P51532-1
SMARCA4	ENST00000643549.1 link	c.3127C>T	p.Arg1043Trp	missense_variant	Exon 22 of 35			ENSP00000493975.1	A0A2R8Y4P4
SMARCA4	ENST00000541122.6 link	c.3127C>T	p.Arg1043Trp	missense_variant	Exon 23 of 35	5		ENSP00000445036.2	P51532-4
SMARCA4	ENST00000643296.1 link	c.3127C>T	p.Arg1043Trp	missense_variant	Exon 22 of 34			ENSP00000496635.1	P51532-4
SMARCA4	ENST00000644737.1 link	c.3127C>T	p.Arg1043Trp	missense_variant	Exon 22 of 34			ENSP00000495548.1	P51532-4
SMARCA4	ENST00000589677.5 link	c.3127C>T	p.Arg1043Trp	missense_variant	Exon 23 of 35	5		ENSP00000464778.1	P51532-3
SMARCA4	ENST00000643995.1 link	c.2539C>T	p.Arg847Trp	missense_variant	Exon 19 of 32			ENSP00000496004.1	A0A2R8YGG3
SMARCA4	ENST00000644963.1 link	c.1771C>T	p.Arg591Trp	missense_variant	Exon 15 of 28			ENSP00000495599.1	A0A2R8YG32
SMARCA4	ENST00000644065.1 link	c.1852C>T	p.Arg618Trp	missense_variant	Exon 15 of 27			ENSP00000493615.1	A0A2R8Y440
SMARCA4	ENST00000642350.1 link	c.1612C>T	p.Arg538Trp	missense_variant	Exon 14 of 27			ENSP00000495355.1	A0A2R8Y6N0
SMARCA4	ENST00000643857.1 link	c.1480C>T	p.Arg494Trp	missense_variant	Exon 13 of 25			ENSP00000494159.1	A0A2R8Y526

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 16

Pathogenic:3

May 31, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 22, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76; 3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SMARCA4 related disorder (ClinVar ID: VCV000436813 / PMID: 23929686). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID:23929686). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 05, 2021

MGZ Medical Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Jan 30, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 04, 2024

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: 32978145, 24658002, Mun2017[article], 23929686) -

SMARCA4-related disorder

Pathogenic:1

Apr 09, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SMARCA4 c.3127C>T variant is predicted to result in the amino acid substitution p.Arg1043Trp. This variant was reported to have occurred de novo in at least two individuals with Coffin-Siris syndrome (Santen et al. 2013. PubMed ID: 23929686; Wei et al 2020. PubMed ID: 32978145; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641751/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A different nucleotide substitution affecting the same amino acid (p.Arg1043Leu) has also been reported de novo in an individual with Coffin-Siris syndrome (Lee et al. 2021. PubMed ID: 34706719). Taken together, the c.3127C>T (p.Arg1043Trp) variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;D;D;.;.;.;.

Eigen

Benign

0.065

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.30

LIST_S2

Pathogenic

0.99

.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Pathogenic

4.6

H;.;.;.;H;H;.;H;H;H;H;H;H;H;H;H;.;.;.;.;.;.

PhyloP100

-0.45

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-6.9

D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.

Polyphen

1.0

D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.

Vest4

0.94

MutPred

0.71

Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);.;Gain of helix (P = 0.0078);.;.;.;.;

MVP

0.94

MPC

3.3

ClinPred

1.0

GERP RS

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over