rs751565055

Positions:

• chr19-11007959-A-G
• chr19-11007959-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_003072.5(SMARCA4):​c.2059A>G​(p.Lys687Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,170 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.85

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ 6.8459 (greater than the threshold 3.09). Trascript score misZ 8.7957 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1553618).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.2059A>G	p.Lys687Glu	missense_variant	14/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.2059A>G	p.Lys687Glu	missense_variant	14/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.2059A>G	p.Lys687Glu	missense_variant	14/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.2059A>G	p.Lys687Glu	missense_variant	14/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.2059A>G	p.Lys687Glu	missense_variant	14/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.2059A>G	p.Lys687Glu	missense_variant	15/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.2059A>G	p.Lys687Glu	missense_variant	14/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.2059A>G	p.Lys687Glu	missense_variant	14/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.2059A>G	p.Lys687Glu	missense_variant	15/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.1471A>G	p.Lys491Glu	missense_variant	11/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.703A>G	p.Lys235Glu	missense_variant	7/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.784A>G	p.Lys262Glu	missense_variant	7/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.544A>G	p.Lys182Glu	missense_variant	6/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.412A>G	p.Lys138Glu	missense_variant	5/25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251228 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135780

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461170 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 726914

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: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 27, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2022	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 470278). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (rs751565055, gnomAD 0.003%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 687 of the SMARCA4 protein (p.Lys687Glu). -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2023

The p.K687E variant (also known as c.2059A>G), located in coding exon 13 of the SMARCA4 gene, results from an A to G substitution at nucleotide position 2059. The lysine at codon 687 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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). Based on the supporting evidence, the association of this alteration with Coffin-Siris syndrome is unknown; however, the association of this alteration with rhabdoid tumor predisposition syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.023
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.2	L;.;.;.;L;L;.;L;L;L;L;L;L;L;L;L;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.26	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;.;N;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.57	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;.;T;.;.;.
Sift4G	Benign	0.37	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.
Polyphen		0.0010	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.
Vest4		0.40
MutPred		0.25		Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);Loss of ubiquitination at K687 (P = 0.0087);.;Loss of ubiquitination at K687 (P = 0.0087);.;.;.;
MVP		0.83
MPC		1.7
ClinPred		0.41	T
GERP RS		5.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.9
Varity_R		0.21
gMVP		0.79

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

Other links and lift over

dbSNP: rs751565055; hg19: chr19-11118635; COSMIC: COSV60802258; COSMIC: COSV60802258;