19-11041512-C-T

Position:

• chr19-11041512-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003072.5(SMARCA4):​c.4376C>T​(p.Thr1459Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. 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:4
• Conservation: PhyloP100: 7.86

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4472C>T	p.Thr1491Ile	missense_variant	31/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4376C>T	p.Thr1459Ile	missense_variant	30/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4472C>T	p.Thr1491Ile	missense_variant	31/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4376C>T	p.Thr1459Ile	missense_variant	30/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4382C>T	p.Thr1461Ile	missense_variant	30/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4286C>T	p.Thr1429Ile	missense_variant	30/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4286C>T	p.Thr1429Ile	missense_variant	29/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4286C>T	p.Thr1429Ile	missense_variant	29/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4286C>T	p.Thr1429Ile	missense_variant	30/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3797C>T	p.Thr1266Ile	missense_variant	27/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3029C>T	p.Thr1010Ile	missense_variant	23/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3011C>T	p.Thr1004Ile	missense_variant	22/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2870C>T	p.Thr957Ile	missense_variant	22/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2738C>T	p.Thr913Ile	missense_variant	21/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.542C>T	p.Thr181Ile	missense_variant	4/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461656 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727142

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2;C3553249:Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Intellectual disability, autosomal dominant 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 20, 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 537775). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1491 of the SMARCA4 protein (p.Thr1491Ile). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2020

The p.T1491I variant (also known as c.4472C>T), located in coding exon 30 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 4472. The threonine at codon 1491 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	0.91
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.8	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.092	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.12	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.84	P;.;D;.;.;.;.;.;.;.;P;.;.;.;.;.;.;D;.;.;.;.;.
Vest4		0.76
MutPred		0.19		.;.;Loss of phosphorylation at T1491 (P = 0.0318);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of phosphorylation at T1491 (P = 0.0318);.;.;.;.;.;
MVP		0.52
MPC		2.2
ClinPred		0.96	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.87

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: rs1555788341; hg19: chr19-11152188;