19-10994889-C-T

Variant names:

• chr19-10994889-C-T
• rs1060502098
• NM_001387283.1:c.1481C>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.1481C>T​(p.Thr494Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,786 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).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.42

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 -5 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18553635).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.1481C>T	p.Thr494Ile	missense_variant	Exon 9 of 36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.1481C>T	p.Thr494Ile	missense_variant	Exon 9 of 35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.1481C>T	p.Thr494Ile	missense_variant	Exon 9 of 36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.1481C>T	p.Thr494Ile	missense_variant	Exon 9 of 35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.1481C>T	p.Thr494Ile	missense_variant	Exon 9 of 35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.1481C>T	p.Thr494Ile	missense_variant	Exon 10 of 35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.1481C>T	p.Thr494Ile	missense_variant	Exon 9 of 34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.1481C>T	p.Thr494Ile	missense_variant	Exon 9 of 34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.1481C>T	p.Thr494Ile	missense_variant	Exon 10 of 35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.893C>T	p.Thr298Ile	missense_variant	Exon 6 of 32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.125C>T	p.Thr42Ile	missense_variant	Exon 2 of 28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.209C>T	p.Thr70Ile	missense_variant	Exon 2 of 27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.-32C>T		upstream_gene_variant				ENSP00000495355.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign: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

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 494 of the SMARCA4 protein (p.Thr494Ile). This variant is not present in population databases (gnomAD no frequency). 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: 408682). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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

Jun 09, 2023

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 does not alter 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) -

Hereditary cancer-predisposing syndrome Benign:1

Oct 25, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.19	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	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.2	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N;.
REVEL	Benign	0.17
Sift	Benign	0.30	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T;.
Sift4G	Benign	0.43	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.
Polyphen		0.073	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.
Vest4		0.27
MutPred		0.48		Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);Gain of catalytic residue at T494 (P = 0.0068);.;
MVP		0.75
MPC		2.4
ClinPred		0.78	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.95

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: rs1060502098; hg19: chr19-11105565;