19-11026328-C-T

Position:

• chr19-11026328-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003072.5(SMARCA4):​c.3197C>T​(p.Thr1066Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,672 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.43

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.33690786).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.3197C>T	p.Thr1066Ile	missense_variant	23/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.3197C>T	p.Thr1066Ile	missense_variant	23/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.3197C>T	p.Thr1066Ile	missense_variant	23/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.3197C>T	p.Thr1066Ile	missense_variant	23/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.3197C>T	p.Thr1066Ile	missense_variant	23/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.3197C>T	p.Thr1066Ile	missense_variant	24/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.3197C>T	p.Thr1066Ile	missense_variant	23/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.3197C>T	p.Thr1066Ile	missense_variant	23/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.3197C>T	p.Thr1066Ile	missense_variant	24/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.2609C>T	p.Thr870Ile	missense_variant	20/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.1841C>T	p.Thr614Ile	missense_variant	16/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.1922C>T	p.Thr641Ile	missense_variant	16/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.1682C>T	p.Thr561Ile	missense_variant	15/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.1550C>T	p.Thr517Ile	missense_variant	14/25			ENSP00000494159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461672 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727148

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1066 of the SMARCA4 protein (p.Thr1066Ile). 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: 537770). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2024

The p.T1066I variant (also known as c.3197C>T), located in coding exon 22 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 3197. The threonine at codon 1066 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-0.071
Eigen_PC	Benign	0.082
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.097	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	Benign	-0.52	T
MutationAssessor	Benign	0.79	N;.;.;.;N;N;.;N;N;N;N;N;N;N;N;N;.;.;.;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.5	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;D;N;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.14	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;D;T;.;.;.;.
Sift4G	Benign	0.087	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.
Polyphen		0.0090	B;.;B;.;.;.;.;.;.;.;B;.;.;.;.;.;.;B;.;.;.;.
Vest4		0.28
MutPred		0.44		Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);Loss of disorder (P = 0.0811);.;Loss of disorder (P = 0.0811);.;.;.;.;
MVP		0.62
MPC		1.6
ClinPred		0.67	D
GERP RS		4.5
Varity_R		0.092
gMVP		0.92

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: rs1555781082; hg19: chr19-11137004; COSMIC: COSV60790521; COSMIC: COSV60790521;