19-10991309-C-T

Variant names:

• chr19-10991309-C-T
• rs1060502079
• NM_001387283.1:c.1405C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_003072.5(SMARCA4):​c.1405C>T​(p.Arg469Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,788 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0460

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1405C>T	p.Arg469Trp	missense_variant	Exon 8 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1405C>T	p.Arg469Trp	missense_variant	Exon 8 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1405C>T	p.Arg469Trp	missense_variant	Exon 8 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1405C>T	p.Arg469Trp	missense_variant	Exon 8 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1405C>T	p.Arg469Trp	missense_variant	Exon 8 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1405C>T	p.Arg469Trp	missense_variant	Exon 9 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1405C>T	p.Arg469Trp	missense_variant	Exon 8 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1405C>T	p.Arg469Trp	missense_variant	Exon 8 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1405C>T	p.Arg469Trp	missense_variant	Exon 9 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.817C>T	p.Arg273Trp	missense_variant	Exon 5 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.49C>T	p.Arg17Trp	missense_variant	Exon 1 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.133C>T	p.Arg45Trp	missense_variant	Exon 1 of 27			ENSP00000493615.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449788 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 720080

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 30, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with tryptophan at codon 469 of the SMARCA4 protein (p.Arg469Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. 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: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SMARCA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 408642). This variant is not present in population databases (ExAC no frequency). -

not provided Uncertain:1

Aug 05, 2024

GeneDx

Significance: Uncertain significance

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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24658002) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.044
FATHMM_MKL	Benign	0.40	N
LIST_S2	Pathogenic	1.0	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.0	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.4	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;D;.;D;.;D;.;D;D
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D
Vest4		0.70
MutPred		0.71		Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);Gain of ubiquitination at K467 (P = 0.0276);
MVP		0.74
MPC		2.5
ClinPred		0.99	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		1.0

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: rs1060502079; hg19: chr19-11101985; COSMIC: COSV60791743; COSMIC: COSV60791743;