NM_001387283.1:c.3086A>G

Variant names:

• chr19-11025426-A-G
• rs1288014090
• NM_001387283.1:c.3086A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001387283.1(SMARCA4):​c.3086A>G​(p.Lys1029Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,772 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 9.10

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in the SMARCA4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 56 curated benign missense variants. Gene score misZ: 6.8459 (above the threshold of 3.09). Trascript score misZ: 8.7957 (above the threshold of 3.09). GenCC associations: The gene is linked to uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3086A>G	p.Lys1029Arg	missense_variant	Exon 22 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3086A>G	p.Lys1029Arg	missense_variant	Exon 22 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3086A>G	p.Lys1029Arg	missense_variant	Exon 22 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3086A>G	p.Lys1029Arg	missense_variant	Exon 22 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3086A>G	p.Lys1029Arg	missense_variant	Exon 22 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3086A>G	p.Lys1029Arg	missense_variant	Exon 23 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3086A>G	p.Lys1029Arg	missense_variant	Exon 22 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3086A>G	p.Lys1029Arg	missense_variant	Exon 22 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3086A>G	p.Lys1029Arg	missense_variant	Exon 23 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2498A>G	p.Lys833Arg	missense_variant	Exon 19 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1730A>G	p.Lys577Arg	missense_variant	Exon 15 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1811A>G	p.Lys604Arg	missense_variant	Exon 15 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1571A>G	p.Lys524Arg	missense_variant	Exon 14 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1439A>G	p.Lys480Arg	missense_variant	Exon 13 of 25			ENSP00000494159.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251016 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460638 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726668

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000679 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1029 of the SMARCA4 protein (p.Lys1029Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 470335). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -

Mar 13, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

May 07, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000012 (3/251016 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Feb 18, 2024

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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Published functional studies suggest this variant results in decreased acetylation levels (PMID: 31291457); This variant is associated with the following publications: (PMID: 24658002, 31291457) -

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

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K1029R variant (also known as c.3086A>G), located in coding exon 21 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 3086. The lysine at codon 1029 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	0.0064
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.083	D
MutationAssessor	Benign	0.84	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.0	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.;.
REVEL	Uncertain	0.41
Sift	Benign	0.041	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.031	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		0.060	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.41
MutPred		0.41		Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);.;Loss of solvent accessibility (P = 0.0083);.;.;.;.;
MVP		0.92
MPC		2.3
ClinPred		0.37	T
GERP RS		4.8
Varity_R		0.23
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1288014090; hg19: chr19-11136102;