19-11060113-C-T

Position:

• chr19-11060113-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_003072.5(SMARCA4):​c.4837C>T​(p.Arg1613Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000643 in 1,398,672 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: 33)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.994

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 -4 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=0.39987138).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4933C>T	p.Arg1645Trp	missense_variant	35/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4837C>T	p.Arg1613Trp	missense_variant	34/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4933C>T	p.Arg1645Trp	missense_variant	35/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4837C>T	p.Arg1613Trp	missense_variant	34/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4843C>T	p.Arg1615Trp	missense_variant	34/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4747C>T	p.Arg1583Trp	missense_variant	34/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4747C>T	p.Arg1583Trp	missense_variant	33/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4747C>T	p.Arg1583Trp	missense_variant	33/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4744C>T	p.Arg1582Trp	missense_variant	34/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.4258C>T	p.Arg1420Trp	missense_variant	31/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3487C>T	p.Arg1163Trp	missense_variant	27/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3469C>T	p.Arg1157Trp	missense_variant	26/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.3331C>T	p.Arg1111Trp	missense_variant	26/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.3097C>T	p.Arg1033Trp	missense_variant	24/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.901C>T	p.Arg301Trp	missense_variant	7/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000656 AC: 1 AN: 152404 Hom.: 0 AF XY: 0.0000124 AC XY: 1 AN XY: 80930

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000916

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000643 AC: 9 AN: 1398672 Hom.: 0 Cov.: 33 AF XY: 0.00000435 AC XY: 3 AN XY: 689892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000206

Gnomad4 NFE exome AF: 0.00000649

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 04, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 470426). This variant has not been reported in the literature in individuals affected with SMARCA4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1645 of the SMARCA4 protein (p.Arg1645Trp). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2023

The p.R1645W variant (also known as c.4933C>T), located in coding exon 34 of the SMARCA4 gene, results from a C to T substitution at nucleotide position 4933. The arginine at codon 1645 is replaced by tryptophan, an amino acid with dissimilar 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.2	L;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.7	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0070	D;.;.;.;.;.;.;.;.;.;D;.;D;D;D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;.
Vest4		0.36
MutPred		0.24		.;.;Loss of helix (P = 0.0167);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of helix (P = 0.0167);.;.;.;.;
MVP		0.65
MPC		2.1
ClinPred		0.97	D
GERP RS		1.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.31
gMVP		0.64

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: rs1370639203; hg19: chr19-11170789;