rs587778684

Variant names:

• chr19-11058800-A-G
• rs587778684
• NM_001387283.1:c.4642A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001387283.1(SMARCA4):​c.4642A>G​(p.Asn1548Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1548S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1 O:1
• Conservation: PhyloP100: 7.49
• Publications: 3 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19640023).
• BP6: Variant 19-11058800-A-G is Benign according to our data. Variant chr19-11058800-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135253.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4642A>G	p.Asn1548Asp	missense_variant	Exon 33 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4546A>G	p.Asn1516Asp	missense_variant	Exon 32 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4642A>G	p.Asn1548Asp	missense_variant	Exon 33 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4546A>G	p.Asn1516Asp	missense_variant	Exon 32 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4552A>G	p.Asn1518Asp	missense_variant	Exon 32 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4456A>G	p.Asn1486Asp	missense_variant	Exon 32 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4456A>G	p.Asn1486Asp	missense_variant	Exon 31 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4456A>G	p.Asn1486Asp	missense_variant	Exon 31 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4453A>G	p.Asn1485Asp	missense_variant	Exon 32 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3967A>G	p.Asn1323Asp	missense_variant	Exon 29 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3196A>G	p.Asn1066Asp	missense_variant	Exon 25 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3178A>G	p.Asn1060Asp	missense_variant	Exon 24 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3040A>G	p.Asn1014Asp	missense_variant	Exon 24 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2895+437A>G		intron_variant	Intron 22 of 24			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.699+437A>G		intron_variant	Intron 5 of 7	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251372 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 16 Uncertain:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 1548 of the SMARCA4 protein (p.Asn1548Asp). This variant is present in population databases (rs587778684, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 135253). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SMARCA4 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

May 21, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Identified in healthy individuals undergoing whole genome sequencing (Bodian et al., 2014); This variant is associated with the following publications: (PMID: 24658002, 24728327) -

Hereditary cancer-predisposing syndrome Benign:1

Mar 31, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.073
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.96	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		7.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.090	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.15
Sift	Benign	0.50	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.74	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.0	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.;.
Vest4		0.30
MutPred		0.48		.;.;Loss of MoRF binding (P = 0.0608);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0608);.;.;.;.;.;
MVP		0.60
MPC		1.1
ClinPred		0.49	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.52
gMVP		0.75
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs587778684; hg19: chr19-11169476;