rs141826721

Variant names:

• chr19-11059882-G-A
• rs141826721
• NM_001387283.1:c.4861G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11059882-G-A
• chr19-11059882-G-C
• chr19-11059882-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001387283.1(SMARCA4):​c.4861G>A​(p.Glu1621Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1621D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.81
• Publications: 4 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4861G>A	p.Glu1621Lys	missense_variant	Exon 34 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4765G>A	p.Glu1589Lys	missense_variant	Exon 33 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4861G>A	p.Glu1621Lys	missense_variant	Exon 34 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4765G>A	p.Glu1589Lys	missense_variant	Exon 33 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4771G>A	p.Glu1591Lys	missense_variant	Exon 33 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4675G>A	p.Glu1559Lys	missense_variant	Exon 33 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4675G>A	p.Glu1559Lys	missense_variant	Exon 32 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4675G>A	p.Glu1559Lys	missense_variant	Exon 32 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4672G>A	p.Glu1558Lys	missense_variant	Exon 33 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4186G>A	p.Glu1396Lys	missense_variant	Exon 30 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3415G>A	p.Glu1139Lys	missense_variant	Exon 26 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3397G>A	p.Glu1133Lys	missense_variant	Exon 25 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3259G>A	p.Glu1087Lys	missense_variant	Exon 25 of 27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3025G>A	p.Glu1009Lys	missense_variant	Exon 23 of 25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.829G>A	p.Glu277Lys	missense_variant	Exon 6 of 8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248550 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: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461522 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727054

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53104

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111976

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Oct 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1621 of the SMARCA4 protein (p.Glu1621Lys). This variant is present in population databases (rs141826721, gnomAD 0.0009%). 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: 408696). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1621K variant (also known as c.4861G>A), located in coding exon 33 of the SMARCA4 gene, results from a G to A substitution at nucleotide position 4861. The glutamic acid at codon 1621 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Missense and in-frame variants in SMARCA4 are known to cause neurodevelopmental disorders; however, such associations with rhabdoid tumor predisposition syndrome including small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) are exceedingly rare (Kosho T et al. Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75; Jelinic P et al. Nat Genet. 2014 May;46(5):424-6). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		9.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.6	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.011	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.
Sift4G	Benign	0.26	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.72	P;.;B;.;.;.;.;.;.;.;P;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.75
MVP		0.92
MPC		1.3
ClinPred		0.69	D
GERP RS		4.3
Varity_R		0.16
gMVP		0.69
Mutation Taster		=39/61	disease causing

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: rs141826721; hg19: chr19-11170558;